SK75898A3 - Novel pyrazole derivatives, preparation method thereof and pharmaceutical compositions containing the same - Google Patents

Abstract

N-benzyl-pyrazole carboxylic acid derivatives of formulae (I) and (XIII) and their salts are new. Ar1 = 2-g2,3-g3,4-g4,5-g5,6-g6-phenyl; Ar2 = 2-w2,3-w3,4-w4,5-w5,6-w6-phenyl; X1 = NR1R2 or OR2; g2-g6, w2-w6 = H, halo, 1-4C alkyl, 1-4C alkoxy, 1-4C alkylthio, CF3 or nitro, provided that at least one of g2-g6 and at least one of w2-w6 are other than H; R1 = H or 1-4C alkyl; R2 = non-aromatic 3-15C carbocycle, optionally substituted by one or more halo or 1-4C alkyl or alkoxy; R3 = H or CH2R6; R4, R5 = H, 1-4C alkyl or CF3; or R4 = H; and R5+w6 = ethylene or trimethylene; R6 = H or, when at least one of g2-g6 is other than 1-4C alkyl, also may be 1-4C alkyl, F, OH, 1-5C alkoxy, 1-5C alkylthio, 1-5C hydroxyalkoxy, CN, 1-5C alkylsulphinyl or 1-5C alkylsulphonyl.

Description

NEW PYRAZOL DERIVATIVES, METHOD OF MANUFACTURE AND PHARMACEUTICAL PARTICULARS WITH THEIR CONTENTS

Technical field

The invention relates to novel pyrazole derivatives and their possible salts, to a process for their preparation and to pharmaceutical compositions containing them.

In particular, the present invention relates to novel pyrazole derivatives that exhibit very good affinity for peripheral cannabinoid receptors, called CB ₂ receptors, and which are useful in the therapeutic field where CB ₂ receptors are involved.

BACKGROUND OF THE INVENTION

^{9 9} -THC is the major active ingredient of Cannabis sativa (Tuner, 1985, In Marijuana 1984, Ed. Harvey, DY, IRL Press, Oxford).

Characterization of cannabinoid receptors has been made possible by the generation of synthetic ligands such as WIN 55212-2 agonists (J. Pharmacol. Exp. Ther., 1993, 264, 1352-1363) or CP-55940 (J. Pharmacol. Exp. Ther., 1988, 247). , 1046-1051).

Many articles describe not only the psychotropic effects of cannabinoids, but also their effects on immune activity (Hollister, L. E., J. Psychoact. Drugs 24, 1992, 159-164). Most in vitro studies have shown immunogenic effects of cannabincides: inhibition of mitogen-induced proliferative responses of T lymphocytes and B lymphocytes (Luo, YD et al., Int. J. Immunopharmacol., 1992, 14, 49-56; Schwartz, H. et al., J Neuroimmunol., 1994, 55, 107-115), the inhibitory activity of cytotoxic T cells (Klein et al., J. Toxicol. Environm. Health, 1991, 32, 465-477), the inhibition of the microbicidal activity of macrophages and the synthesis of TNFalpha ( Arata, S. et al., Life Sci., 1991, 49, 473-479), Fisher-Stener et al., J. Pharm. Exp. Ther., 1993, 267, 1558 - 1565), inhibition of the cytolytic effect and TNFalpha production of certain lymphocytes (Kusher et al., Cell. Immun., 1994, 154, 99-108). Conversely, certain studies have shown amplifying effects: increasing the bioactivity of interleukin-1 by macrophages residing in mice or by line differentiated cell macrophages using ornose

3C983 / H

TNFalpha (Zhu et al., J. Pharm. Exp. Ther., 1994, 270, 1334-1339, Shivers, S. C. et al., Life Sci., 1994, 54, 1281-1289).

The effects of cannabinoids are due to the interaction with specific high affinity receptors that are present at the central level (Devane et al., Molecular Pharmacology, 1988, 34, 605-613) and peripheral (Nye et al., The Journal of Pharmacology and Experimental Therapeutics, 1985, 234, 784-791, Kaminski et al., Molecular Pharmacology, 1992, 42, 736-742, Munro et al., Nature 1993, 365, 61-65).

The central effects are dependent on a first type of cannabinoid receptor (CBU, which are present in the brain. Furthermore, Munro et al. (Nature 1993, 365, 61-65) have cloned a second cannabinoid receptor coupled to proteins G, called _CB2, which is The presence of CB ₂ cannabinoid receptors in lymphoid cells may explain the immunomodulation performed by cannabinoid receptor agonists listed above.

Numerous pyrazole derivatives have been described in the literature, in particular EP-A268 554 and DE-A-3 910 248 claim pyrazoles with herbicidal properties, EP-A-430 186 and JP-A-3 031 840 claim compounds suitable for photography and EPA-418 845 claims pyrazoles having anti-inflammatory, analgesic and antithrombotic effects.

Pyrazolecarboxamide derivatives are also described, in particular, in patent applications EP-A-0 289 879 and EP-A-0 492 125; these compounds exhibit insecticidal properties.

In addition, patent application EP-A-0 477 049 describes pyrazole-3-carboxamide derivatives of formula (1):

3C983 / H in which, for example:

R 1 represents an aryl group differently substituted,

R 11 represents a hydrogen atom or a (C 1 -C ₄ ) alkyl group,

R 11 represents a hydroxyl group, a (C 1 -C ₆ ) alkoxy group, an amino group,

Riv represents a hydrogen atom or a (C 1 -C ₆ ) alkyl group,

Rv represents a phenyl group differently substituted, n is 0, 1, 2 or 3.

These compounds exhibit central nervous system activity and, in particular, interaction with the neurotensin receptor.

In addition, patent applications EP-A-576 357 and EP-A-658 546 disclose pyrazole derivatives with affinity for cannabinoid receptors. The application EP-A-656 354 claims inter alia, N-piperidino-5- (4-chlorophenyl) -1- ₍₂ '4-dichloro-phenyl) -metylpyrazol-

3-carboxamide or SR 141716, and pharmaceutically acceptable salts thereof, which show very good affinity for central cannabinoid receptors.

SUMMARY OF THE INVENTION

Recently, several pyrazole derivatives have been found which have an increased affinity for human CB2 receptors and are specific for these receptors as well as potent immunomodulators.

In the following description, "increased affinity for the human CB ₂ receptor" means an affinity characterized by an affinity constant generally less than 100 nM going up to 0.1 nM and the term "specific" refers to compounds whose affinity constant for the CB ₂ receptor is generally at least 10 times less than the affinity constant for CB 1 receptors.

According to one aspect of the present invention, there are provided compounds of formula (I)

30983 / H

in which symbol

X 1 is -NR 1 R 6 or OR ₂ , g ₂ , g ₃ , g ₄ , gs, g 6 and w ₂ , w ₃ , w ₄ , w ₅ , w ₆ groups are identical or different and are each independently hydrogen, atom halogen, (C ₁ -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, trifluoromethyl, nitro, (C 1 -C ₄ ) alkylthio; with the proviso that at least one of substituents g ₂ , g ₃ , g ₄ , g ₅ , g ₆ and at least one of substituents w ₂ , w ₃ , w ₄ , W 5, W 6 are different from hydrogen,

R is H or (C _r C ₄₎ alkyl group,

R ₂ represents a carbocyclic non-aromatic radical having (C ₃ -C ₁₅ ) carbon atoms, unsubstituted or substituted one or more times with substituents selected from the group consisting of halogen, (C 1 -C ₄ ) alkyl or C ₁ -C ₄ ) alkoxy,

R ₃ represents a hydrogen atom or a group -CH ₂ -R 6,

R ₄ and R ₅ are each independently hydrogen, (C 1 -C ₄ ) alkyl or trifluoromethyl, or R ₄ is hydrogen and R _{5 and} w ₆ together form an ethylene or trimethylene radical,

R ₆ represents a hydrogen atom or when the substituents g ₂ , g ₃ , g ₄ , g ₅ and / or g 6 are other than a (C 1 -C ₄ ) alkyl group, R 6 represents a hydrogen atom, a (C 1 -C ₄ ) alkyl group, an atom fluoro, hydroxy, (C 1 -C ₅ ) alkoxy, (C 1 -C 5) alkylthio, hydroxy (C 1 -C 5) alkoxy, cyano, (C 1 -C 5) alkysulfinyl, (C 1 -C 5) alkylsulfonyl,

3C983 / H and their possible salts.

Where the compound of formula (I) of the present invention contains one or more asymmetric carbons, the invention also includes optical isomers and racemates.

Optional salts of the compounds of formula (I) are pharmaceutically acceptable acid addition salts such as hydrochloride, hydrobromide, sulfate, hydrogensulfate, dihydrogen phosphate, methanesulfonate, methylsulfate, maleate, oxalate, fumarate, naphthalenesulfonate, glyconate, gluconate, paronate, citrate, citrate, citrate or benzenesulfonate.

Carbocyclic non-aromatic radicals having a carbon number of C3-C15 represent mono- or polycyclic, fused, bridged or spiranic radicals, saturated or unsaturated or terpenic. These radicals are optionally substituted one or more times with a group selected from (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or halogen, and in the case of terpenes or terpenic radicals, for example bornyl, menthyl or mentenyl, alkylated groups terpene are not considered as substituents.

Monocyclic radicals include cycloalkyls such as cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclododecyl unsubstituted or substituted one or more times with (C 1 -C 4) alkyl, (C 1 -C 4) alkoxy or halogen such as 2-methylcyclohex-1 2,6-dimethyl-cyclohex-1-yl, 2,2,6,6-tetramethylcyclohex-1-yl.

Di- or tricyclic fused, bridged or spiranic or terpenic radicals include, for example, bicyclo [2.2.1] heptyl or bicyclo [3.2.1 joctyl, bicyclo [2.2.2] octyl, tricyclo [5.2.1.0 ^2,6 ] decyl, spiro [5,5] -undecyl, bicyclo [2.2.2] oct-2-en-5-yl, tricyclo [2.2.1,0 ^2,6 ] -hept-3-yl, said radicals being unsubstituted or substituted once or multiple times with a (C1-C4) alkyl group, a halogen atom, or a (C1-C4) alkoxy group such as 1,3,3-trimethylbicyclo [2.2.1] hept-2-yl or fenchyl.

30983 / H

The described alkyl or alkoxy groups in the present invention are straight or branched. Halogen is understood to mean chlorine, bromine, fluorine or iodine.

According to the present invention, compounds of formula (I) are preferred in which the symbol:

X 1 is -NR 4, g ₂ , g ₃ , g ₄ , g ₆ , g 6 and w ₂ , W 3, w ₄ , w ₅ , W 6 are identical or different and are each independently hydrogen, halogen, (C 1 -C 4) alkyl, _(Ci-C4) alkoxy, trifluoromethyl, nitro, (C _r C ₄₎ alkylthio; with the proviso that at least one of g ₂ , g ₃ , g ₄ , gs, g 6 and at least one of w ₂ , w ₃ , w ₄ , w ₅ , w ₆ are different from hydrogen,

R ₁ represents a hydrogen atom or a (C 1 -C ₄ ) alkyl group,

R ₂ is a carbocyclic aromatic radical (C3-C15) -alkyl, unsubstituted or substituted one or more times with substituents selected from the group consisting of halogen, _(Ci-C4) alkyl or _(Ci-C4) alkoxy,

R ₃ represents a hydrogen atom or a group -CH ₂ -R ₆ ,

R ₄ and R ₅ are each independently hydrogen, (C _{r C4)} alkyl or a trifluoromethyl,

R 6 represents a hydrogen atom, a methyl or ethyl group, and any salts thereof.

Among the compounds of formula (I) wherein X 1 is NR 1 R ₂ , those in which R 1 is hydrogen are preferred.

Among the compounds of formula (I) in which Χί is NR 1 R ₂ or -OR ₂ , those in which R ₂ represents the 1,3,3-trimethylbicyclo [2.2.1] hept-2-yl radical are preferred or bicyclo [3.2.1] oct-3-yl radical.

Among the compounds of formula (I) are preferred those compounds in which R ₃ represents H or CH ₂ R ₆ where R ₆ is hydrogen.

30783 / H

Among the compounds of formula (I), those in which R ₄ and R ₅ each represent either a hydrogen atom or R ₄ represents a hydrogen atom and R 5 represents a (C 1 -C 4) alkyl group are preferred.

Among the compounds of formula (I), those in which g ₂ , g 5 and g 6 are hydrogen and g _{3 and} g ₄ are as defined above for compounds of formula (I) are preferred.

Among the compounds of formula (I) are preferred those compounds wherein the group W ₅ and W 6 represents -H, w ₄ is a halogen atom, _(Ci-C4) alkyl, (C 1 -C 4) alkoxy, trifluoromethyl, or ( C 1 -C 4 alkylthio and either w _{2 and} w ₃ are each hydrogen or one is hydrogen and the other is halogen, (C 1 -C 4) alkyl or trifluoromethyl.

The set of preferred compounds of the present invention is a set of compounds of formula (Ia)

wherein the substituents

R _h R ₂ are the same as defined for compounds of formula (I),

R _3a represents a hydrogen atom or a group -CH ₂ -R 6a,

R _6a is H or provided that the substituents g _3a and g 4 are other than _a (C 1 -C 4) alkyl,

R _6a represents a hydrogen atom, a methyl group, an ethyl group, g _3a represents a hydrogen atom, a halogen atom, a (C 1 -C 4) alkyl group or trifluoromethyl,

30983 / H g _4a represents a halogen atom, (C 1 -C 4) alkyl or trifluoromethyl, w _4a represents a halogen atom, (C ₁ -C ₄ ) alkyl or trifluoromethyl, w _{2a and 3a} groups represent each hydrogen atom or one represents a hydrogen atom and the other represents a halogen atom, a (C 1 -C ₄ ) alkyl group or trifluoromethyl, and possible salts thereof.

Among these compounds, those compounds of formula (Ia)

in which the substituents:

R 1, R ₂ are as defined for compounds of formula (I),

R _3a is the same as defined for compounds of formula (Ia), g ' _3a represents a hydrogen atom, a chlorine atom, a fluorine atom, a methyl group or a trifluoromethyl group, g' _4a represents a chlorine atom, a fluorine atom, a methyl group or a trifluoromethyl group; w ' _4a represents a chlorine atom, a fluorine atom, a methyl group or trifluoromethyl, w' _2a and w ' _3a each represent a hydrogen atom or one represents a hydrogen atom and the other represents a chlorine atom, a fluorine atom, a methyl group or trifluoromethyl;

30983 / H and their possible salts are particularly preferred.

Compounds of formula (Ia ') in which the substituent:

R 1 represents a hydrogen atom,

R ₂ is a 1,3,3-trimethyl [2.2.1] hept-2-yl radical or a bicyclo [3.2.1] oct-3-yl,

R _3a is defined for compounds of formula (Ia), w'2a, w ' _3a , w' _4a , g'3a and g ' _4a are defined for a compound of formula (Ia).

as well as their possible salts.

Particularly preferred are compounds of formula (Ia) wherein the substituent:

g ' _3a represents a hydrogen atom, a chlorine atom, a fluorine atom or a methyl group, g' _4a represents a chlorine atom, a fluorine atom or a methyl group, w ' _4a represents a chlorine atom, a fluorine atom or a methyl group, w' _2a and w ' _3a represent each a hydrogen atom or one represents a hydrogen atom and the other represents a chlorine atom, a fluorine atom or a methyl group,

R 1, R ₂ and R _3a are as defined for compounds of formula (Ia ') as well as their possible salts.

Another set of preferred compounds of the present invention is a set of compounds of formula (1b)

30983 / H wherein the substituents:

R 1, R 2 are the same as defined for compounds of formula (I),

R _{3, and} wi, w _3a, w _4a, g _3a and g _4a are as defined for a compound of formula (Ia),

R _5b represents a (C 1 -C 4) alkyl group, as well as any salts thereof.

Among these compounds, those compounds of formula (Ib)

(b) wherein the substituents:

R 1, R 2 are the same as defined for compounds of formula (I), R _3a is the same as defined for compounds of formula (Ia), w ' _2a , w' _3a , w ' _4a , g'3a and g' _4a are defined for compounds of formula (Ia),

R ' _5b represents a methyl group, and any salts thereof are particularly preferred.

Particularly preferred are compounds of formula (1b ')> wherein the substituent:

R 1 represents a hydrogen atom,

R2 represents a 1,3,3-trimethylbicyclo [2.2.1] hept-2-yl radical or a bicyclo [3.2.1] oct-3-yl radical,

R _3a is defined for compounds of formula (Ia),

30983, Ή

R _5b is methyl, n _'2, n' _3, n _'4, G ₃ and G ₄ are as defined for a compound of formula (Ia).

as well as their possible salts.

Particularly preferred are compounds of formula (1'b) wherein the substituent:

g ' _3a represents a hydrogen atom, a chlorine atom, a fluorine atom or a methyl group, g' _4a represents a chlorine atom, a fluorine atom or a methyl group, w ' _4a represents a chlorine atom, a fluorine atom or a methyl group, w' _2a and w ' _3a represent each a hydrogen atom or one represents a hydrogen atom and the other represents a chlorine atom, a fluorine atom or a methyl group,

R 1, R 2, R 3a and R 5a are as defined for the compounds of formula (1b ') as well as their optional salts.

Another set of preferred compounds of the present invention is a set of compounds of formula (1c)

wherein the substituents

R ₂ is as defined for the compounds of formula (I),

R _3a , w _2g , w _3a , w _4a , g _{3a and 4a} are defined for compounds of formula (Ia).

3 (983 / H as well as their possible salts).

Another aspect of the present invention is a process for preparing compounds of formula (I) and salts thereof, comprising:

1. acts on a functional pyrazole-3-carboxylic acid derivative of the general formula (II):

wherein the substituents w _2, w _3, w _4, w _5, w _6, g _2, G 3, g _4, g with 96, R 3, R ₄ and R ₅ are as defined for the compounds of formula (I), a compound of formula (XXIV )

H-X 1 (XXIV) wherein X 1 is as defined for compounds of Formula (I),

2. and optionally the compound thus obtained is converted into one of its salts.

One of the methods of the present invention (Method A) is suitable for the preparation of compounds of formula (I) wherein X 1 is represented by NR 1 R.

This method consists of:

1. treatment of a functional pyrazole-3-carboxylic acid derivative of the formula II as defined above with an amine of the formula:

HNR 1 R 2 (III) wherein R 1 and R ₂ are as defined for compounds of formula (I),

2. and optionally the compound thus obtained is converted into one of its salts.

30983 / H

As a functional acid derivative, acid chloride, anhydride, mixed anhydride, alkyl ester of C 1 -C 4 carbon atoms in which the alkyl chain is straight or branched, an active ester such as a p-nitrophenyl ester or a free acid suitably activated, such as Ν, Ν-dicyclohexylcarbodiimide or benzotriazol-1-yloxytris (dimethylamino) phosphonium (BOP) hexafluorophosphate.

Also, in process A of the preparation of the present invention, pyrazole-3-carboxylic acid chloride obtained by reacting thionyl chloride with an acid of formula (II), with an amine of formula HNR-R ₂ , can be reacted in an inert solvent such as chlorinated solvent (e.g. , dichloroethane, chloroform), an ether (e.g. tetrahydrofuran, dioxane) or an amide (e.g. N, N-dimethylformamide) under an inert atmosphere at a temperature between 0 ° C and ambient temperature in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine.

A variant of process A of the present invention consists in preparing a mixed acid anhydride of formula (II) in the presence of a base such as triethylamine and reacted with an amine NHR-R ₂ , in a solvent such as dichloromethane under an inert atmosphere at ambient temperature at room temperature. in the presence of a base such as triethylamine.

Another method of preparation (Method B) of the present invention is the preparation of compounds of formula (I) wherein Χ _Ί is -OR ₂ .

This method consists of:

1. treating a functional pyrazole-3-carboxylic acid derivative of the formula II as defined above with an alcohol of the formula:

HO-R ₂ (XIV) wherein R ₂ is as defined for compounds of formula (I), and optionally the compound thus obtained is converted to one of its salts.

As a functional derivative of acid (II), an acid chloride, anhydride, mixed anhydride or free acid suitably activated, for example Ν, Ν-dicyclohexylcarbodiimide or hexafluorophosphate benzotriazol-1-yloxytris (dimethylamino) phosphonium (BOP), can be used.

30983 / H

Also, in process B of the preparation of the present invention, pyrazole-3-carboxylic acid chloride obtained by reacting thionyl chloride with an acid of formula (II) with an alcohol of formula HO-R2 can be reacted in either an inert solvent such as a chlorinated solvent (e.g. dichloroethane, chloroform), an ether (e.g. tetrahydrofuran, dioxane) or an amide (e.g. N, N-dimethylformamide) under an inert atmosphere at a temperature between 0 ° C and ambient temperature in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine; ambient in the presence of 4-dimethylaminopyridine.

A variant of the process of Preparation A of the present invention consists in preparing a mixed acid anhydride of formula (II) by reacting ethyl chloroformate with an acid of formula (II) in the presence of a base such as triethylamine and reacted with an alcohol HO-R ₂ in a solvent such as dichloromethane; under an inert atmosphere, at ambient temperature in the presence of a base such as triethylamine.

During preparation at any stage of the compounds of formula (I), and in particular in the preparation of intermediates of formula (II), it may be necessary and / or desirable to protect functional reaction or sensitive groups such as amino, hydroxy or carboxy groups present in any of the molecules concerned. . This protection is accomplished using conventional protecting groups such as those described in Protective Groups in Organic Chemistry, J. F. W. McOmie, Bd. Plenum Press, 1973 and in Protective Groups in Organic Synthesis by T. W. Greene and P. G. M. Wutts, Ed. John Wiley and Sons, 1991. The elimination of the protecting groups may be carried out at a suitable subsequent stage using methods known to those skilled in the art which are not affected by the residues of the molecules in question.

The compound of formula (I) obtained is isolated by conventional techniques.

Depending on the nature of the substituents, the compound of formula (I) may optionally be converted into a salt. The salts are prepared by treatment with an acid in an organic solvent. Treatment of an acid in the same solvent with a free base dissolved, for example, in an ether such as diethyl ether or an alcohol such as propan-2-ol or acetone or dichloromethane affords the corresponding salt, which is isolated by conventional techniques.

30983 / H

Thus, for example, hydrochloride, hydrobromide sulfate, hydrogensulfonate, dihydrogen phosphate, methanesulfonate, oxalate, maleate, fumarate, naphthalenesulfonate, benzenesulfonate are prepared.

The compounds of formula (II) are prepared by various methods.

Compounds of formula (II) wherein R 3 is the same as R ' ₃ and is hydrogen or -CH ₂ -R 6 in which R 6 is hydrogen or (C 1 -C 4) alkyl are prepared according to the following: Scheme 1:

3C983 / H

SCHEME 1

(IN)

COOAlk

COOH (VIII), CH ₃ COOH

M = Na, K, Li

Alk = CH ₃ , CH ₂ CH ₃

Hal = Cl, Br, I

R ₃ = H, CH _3, (CH -tCj-CJalkyl

g ₆ Οθ M® o

II

C — C-COOAlk nh ₂ nh ₂ .h ₂ o, ch ₃ cooh

H-N-NH-C

COOAlk

(VII): R ₄ = H

30583 / H

The first stage of _the even consists in preparing an alkali metal salt of the acetophenone derivative of formula (IV) wherein R _'3 is hydrogen or -CH 2 R 6, wherein R ₆ is H or (C1C ₄₎ alkyl group a group g _2, g _3, g 4, g ₆ and g are as defined for (I) and then adding an equimolar amount of diethyl oxalate (step bi) to give the ketoester salt of formula (V).

In a particular case where the group R ' ₃ = H, the alkali metal will preferably be sodium (M = Na) and the ketoester salt (V, Alk = CH ₃ ) will be obtained as described in Bull. Soc. Chim. Fr., 1947, 14, 1098 using sodium methylate in methanol to carry out step a) Potassium tert-butylate in ethanol can also be used in step a to obtain a derivative of formula (IV), then diethyl oxalate is added as described above. . The reaction is carried out at the reflux temperature of the solvent. This gives a compound of formula (V) wherein M = K and Alk = CH ₂ CH ₃ .

In a particular case where the group R ' ₃ = H, the alkali metal will preferably be lithium (M = Li) and the keto ester salt (V, Alk = CH ₂ CH ₃ ) is obtained as described in J. Heterocyclic. Chem., 1989, 26, 1389-1392 using the lithium salt of hexamethyldisilazane in an inert solvent such as diethyl ether or cyclohexane to perform step a.

In step C1, the compound of formula (V) is thus prepared and the excess hydrazine (hydrazine monohydrate or aqueous hydrazine solution) is heated to reflux temperature. Precipitation from ice water gives the pyrazole-3-carboxylates of formula (VI).

In step di, the compound of formula (VI) thus obtained is treated with a strong base such as sodium hydride or sodium amide in a solvent to obtain an anion which reacts with a compound of formula (VII) in which Hal represents a halogen atom, preferably chlorine, bromine or iodine, R 4 represents a hydrogen atom and the groups w ₂ , w ₃ , w ₄ , W 5, w ₆ and R 5 are as defined for compounds of formula (I) for the preparation of a compound of formula (IX). Preferably, the reaction is carried out in toluene at a temperature between ambient temperature and the reflux temperature of the solvent in such a way as to obtain the most desired compound of formula (IX). When the reaction is carried out in N, N30983 / H dimethylformamide at a temperature between 0 ° C and ambient temperature, most formation of the positional isomer of formula (XI) is observed.

(XI)

Alternatively, according to step e _{1: a} compound of formula (V) and an excess of a hydrazine derivative of formula (VIII) in which the groups R ₄ , R ₅ , w ₂ , w ₃ , w ₄ , w ₅ , w ₆ are defined for the compounds of formula (I), are heated to reflux temperature of acetic acid; precipitation from ice water gives compounds of formula (IX).

In step fi by hydrolysis of the compounds of formula (IX), in an alkaline medium and after acidification, the desired compounds of formula (II) are obtained. The hydrolysis is carried out, for example, using an alkali metal hydroxide such as potassium hydroxide, sodium hydroxide or lithium hydroxide in an inert solvent such as water, methanol, ethanol, dioxane or a mixture of these solvents at a temperature from 0 ° C to the reflux temperature of the solvent.

Preferably, compounds of formula (IX) wherein R ₄ is hydrogen are prepared using step c1 and then step di as described above.

Preferably, compounds of formula (IX) wherein R ₄ and R ₅ are different from hydrogen are prepared using step ei as described above.

Preferably, compounds of formula (IX) are prepared in which R ' ₃ = CH ₂ - (C ₁ -C ₄ ) alkyl either when R ₄ and R ₅ are different from hydrogen, starting from the compounds of formula (IX) themselves or when

30983 / H R ₄ = H, starting from a compound of formula (VI) according to the following Scheme 2:

SCHEME 2

br

▼

R / W, R ₄ and R TH

Alk = CH ₃ , CH _? CH ₃ Alk 1 = (C 1 -C 6 alkyl _{) 3} = CH ₃ -C 1-6 alkyl

COOAlk

Step a2 consists of the preparation of a 4-bromomethylpyrazole-3-carboxylate of formula (X) by the action of N-bromosuccinimide on a compound of formula (VI) or (IX) in which the group R'3 is methyl. The reaction is carried out in an inert solvent such as carbon tetrachloride in the presence of dibenzoyl peroxide at the reflux temperature of the solvent.

When a compound of formula (VI) is used, the bromination in step a is preferably carried out. a compound whose pyrazole nitrogen is protected (Y is an N-protecting group). Classic N-protecting groups such as tert-butoxycarbonyl are well known to those skilled in the art as N-protecting groups.

30983 / H

Stage b? It comprising preparing a compound of formula (VI) or (IX) in which R'3 is -CH 2 (C ₄₎ alkyl group, reaction with an organocuprate (Alk ^ CuLi, wherein Alk is (C 1 -C The reaction is carried out as described in patent application EP-A-0 658 546.

Alternatively, if a compound of formula (VI) with a protected pyrazole nitrogen is used, then after step b? eliminates the N-protecting group by methods known to those skilled in the art.

Compounds of formula (II) wherein R ₄ is hydrogen and R 3 = R 3 and is -CH 2 -R 6 wherein R 6 is other than hydrogen or other than (C ₁ -C ₄ ) alkyl are prepared according to the following scheme 3:

3G / 83 / H

SCHEME 3

COOAlk

(XVIII) ϋ ³

I ^T Br

I

COOAlk XVI

(XIX)

Alk = CH ₃ , CH ₂ CH ₃ r-H or (C 1 -C 4 alkyl A = H or a cation

(II): R, = ^R 3 ^{SR. = H}

3G983 / H

In step ai, the nitrogen atom of the compound of formula (VI) (R ' ₃ = CH ₃ ) is protected with an N-protecting group such as tert-butoxycarbonyl (Boe), by methods known to those skilled in the art.

Step b ₃ consists in the preparation of the 4-bromomethylpyrazole-3-carboxylate of the general formula (XVI) by the method described in step a) above. of the scheme 2.

In step c ₃ by treating compound of formula (XVI) with a compound of the formula Re - and (XVII), wherein R e as defined in formula (I) is other than hydrogen or (C 1 -C 4) alkyl and A represents a hydrogen atom or a cation such as an alkali metal or alkaline earth metal cation or a quaternary ammonium group such as tetraethylammonium.

To prepare a compound of formula (XVIII) in which R 6 is (C 1 -C 5) alkoxy or hydroxy (C 1 -C 5) alkoxy, a C 1 -C 5 alcohol or a C 1 -C 5 dialcohol is used as the reactant of the formula (XVII). carbon atoms in the presence of a non-nucleophilic base such as a metal hydride such as sodium or potassium hydride. Depending on the R e values, a mixture of esters can be obtained in step c _{3 of the} process according to the invention, which is saponified in step f ₃ to give the acid of the general formula (II).

For the preparation of a compound of formula (XVIII) in which R 6 is (C 1 -C 5) alkylthio, a thioalcohol having 1 to 5 carbon atoms is used as a reactant of formula (XVII) in the presence of a non-nucleophilic base such as a metal hydride such as sodium or potassium hydride.

If desired, it is possible to convert the ester of formula (XVIII) obtained in step c ₃ in which R ₆ is a (C 1 -C 5) alkylthio group by treatment with an oxidizing agent such as water saturated with oxygen or metachloroperbenzoic acid to give a compound of formula ( XVIII) wherein R 6 is (C 1 -C 5) alkylsulfonyl or (C 1 -C 5) alkylsulfonyl.

A quaternary ammonium cyanide such as tetraethylammonium cyanide or a metal cyanide such as sodium cyanide may be used as a reactant of the general formula (XVII) to prepare a compound of formula (XVIII) wherein R 6 is cyano; in the latter case, the nucleophilic substitution reaction of step c ₃ is carried out in the presence of a phase change catalyst

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For a compound of formula (XVIII), wherein R _a is fluoro, may be used as reagent of formula (XVII) fluorination agent; the fluorinating agent may be a metal fluoride, for example potassium fluoride, used in the presence of a complexing agent such as Kryptofix®.

For the preparation of a compound of formula (XVIII) in which R ₆ = OH, an alkali metal or alkaline earth metal hydroxide such as sodium hydroxide or potassium hydroxide is used as reactant (XVII).

In step d ₃ , the N-protecting group is removed by methods known to those skilled in the art.

In step e ₃ , the compound of formula (XIX) thus obtained is treated with a strong base such as sodium hydride or sodium amide in a solvent to give an anion which is reacted with a compound of formula (VII) wherein Hal is halogen, preferably chlorine bromine or iodine, R ₄ represents a hydrogen atom and w ₂ , w _3, w ₄ , w ₅ , w ₆ and R ₅ are as defined for compounds of formula (I) to give a compound of formula (XX) ). The reaction is preferably carried out in toluene at a temperature comprised between ambient temperature and the reflux temperature of the solvent so as to obtain the predominantly expected compound of formula (XX). When the reaction is carried out in N, N, -dimethylformamide at a temperature comprised between 0 ° C and ambient temperature, the formation of the positional isomer of formula (XXIII) is predominantly observed:

In step _f3 the expected compounds of formula (XX) in an alkaline medium followed by acidification gives the expected compound of formula (II). The hydrolysis is carried out using, for example, an alkali metal hydroxide such as

3C983 / H potassium hydroxide, sodium hydroxide or lithium hydroxide in an inert solvent such as water, methanol, ethanol, dioxane or a mixture of these solvents at a temperature between 0 ° C and the reflux temperature of the solvent.

Compounds of formula (II) wherein R ₃ = R ₃ a represents a group CH ₂ -R 6 wherein R ₆ is other than hydrogen or other than (C 1 -C 4) alkyl and R ₄ and R 5 are not hydrogen are prepared according to Scheme 4 below, in which Alk represents a methyl group or an ethyl group.

Scheme 4

br

Y

c.4 (H): R ^R ^ etRRR RRss -Br

Stage a ₄ consists in the preparation of 4-bromomethylpyrazole-3-carboxylate of general formula (XXI) by the method described above in step 1 of Scheme 2.

3 C-983 / H

In step b ₄ by treating compound of formula (XXI) with a compound of formula R6 --A (XVII), as defined above, by methods described in step c of scheme ₃ 3rd

In step c ₄ , hydrolysis of the compounds of formula (XXII) in an alkaline medium and then acidification affords the expected compounds of formula (II). The hydrolysis proceeds according to the methods described in stage fi of scheme 1.

In step di Scheme 1 or in step e ₃ of Scheme 3, the reaction of a compound of formula (VI) or a compound of formula (XIX) with the halogenated derivative of formula (VII) can give a mixture of variable proportions of the compounds of formula (IX ) or compounds of formula (XX) and their corresponding isomers of formula:

or

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The two isomers (IX) and (XI) or the two isomers (XX) and (XXIII) may be separated by chromatography on silica gel by conventional methods. The two isomers (IX) and (XI) or (X) or (XXIII) are characterized by their NMR spectrum, in particular by the study of the Overhauser effect (N.O.E.).

It is also possible to carry out the process step of the invention or the step f ₃ as described in Scheme 1 or Scheme 3 on a mixture of isomers to obtain a mixture of the acid of formula (II) and its isomer of formula:

(XII)

The mixture of the two isomers (II) and (XII) is applied according to the process of the invention described above to give a mixture of a compound of formula (1) wherein R ₄ = H and its isomer of formula:

(ΧΙΠ)

Thereafter, the two isomers are separated by conventional methods, such as silica gel chromatography or crystallization, to finally obtain the compound of formula (I) of the invention.

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A further object of the present invention are compounds which are intermediates of the process of the invention for the preparation of compounds of formula (I) having the formula:

in which:

X1, g2, g3. g4, gs w ₂ , w ₃ , w ₄ , w ₅ , w ₆ , R ₃ and R ₅ are as defined for the compounds of formula (I) and their possible salts.

A further object of the present invention is a process for the preparation of compounds of intermediates of formula (II) and compounds of formula (XII) which can be used to prepare compounds of formula (1) wherein R ₄ = H and compounds of formula (XIII). This method consists of:

1. treating a compound of the general formula:

COOAlk (XXV) wherein g ₂ , g ₃ , g ₄ , g ₅ , g ₆ and R ₃ are as defined for the compounds of formula (I) and Alk represents a methyl group or an ethyl group,

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(VII) wherein w ₂ , w ₃₁ w ₄ , w ₅ , w ₆ , and R ₅ are as defined for the compounds of formula (I) and Hal represents a halogen atom to obtain:

- either when the reaction is carried out in toluene at a temperature between ambient temperature and the reflux temperature of the solvent, the compound of formula (XXVI):

(XXVI)

- or, when the reaction is carried out in Ν, Ν-dimethylformamide at a temperature between 0 ° C and ambient temperature, a compound of the general formula:

(XXVII)

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2. hydrolyzes in an alkaline medium either a compound of formula (XXVI) or a compound of formula (XXVII) to give:

- either a compound of formula (II, R ₄ = H):

(II: R ₄ = H)

- or a compound of formula (XII):

(ΧΠ)

A further object of the invention is a process for the preparation of compounds of formula (XIII) and salts thereof, which comprises the following steps:

1. a functional acid derivative of the general formula:

(ΧΠ)

3C983 / H in which G _2, G 3, g _4, gs, g6, _{w2, w3, w4, w5,} w _6, R ₃ and R ₅ are as defined for the compounds of formula (I) , a compound of the formula:

H - Xi (XXIV) wherein X 1 is as defined for compounds of formula (I) to give a compound of formula (XIII):

(XIII)

And optionally converting the compound to one of its salts.

The benzyl halides of formula (VII) are known or prepared by known methods. In general, compounds of formula (VII) in which Hal represents a bromine atom may be prepared by treatment of the corresponding methylbenzene derivatives with N-bromosuccinimide in the presence of dibenzoyl peroxide. It is also possible to prepare benzyl bromide starting from the corresponding benzyl alcohol by treatment with hydrobromic acid in solution in water or acetic acid. It is also possible to use phosphorus tribromide on the corresponding benzyl alcohol to prepare a compound of formula (VII) in which Hal represents a bromine atom.

Compounds of formula (VII) in which Hal represents an iodine atom may be prepared by treatment of a compound of formula (VII) in which Hal represents a chlorine atom in a solvent such as acetone or butane by treatment with sodium iodide.

2-one.

Compounds of formula (VII) in which Hal represents a chlorine atom may be prepared by treatment of the corresponding benzyl alcohol with thionyl chloride.

In particular, it is also possible to prepare compounds of formula (VII) wherein R 5 is trifluoromethyl and Hal is chlorine by the method described in J. Fluorine Chem., 1986, 32, 4, 361-366.

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It is also possible to prepare compounds of formula (VII) wherein R ₅ is trifluoromethyl, from the corresponding alpha- (trifluoromethyl) benzyl alcohols by the methods described above, alpha (trifluoromethyl) benzyl alcohols may be prepared according to Tetrahedron, 1989, 45, 5, 1423 or J. Org. Chem. 1991, 56, 1, 2.

Compounds of formula (VIII) are known or prepared by known methods, such as those described in J. Org. Chem., 1988, 53, 1768, 1774 or in J. Am. Chem. Soc., 1958, 80, 6562-6568.

The amines of formula HNR3 are either commercially available or are described in the literature or prepared by known methods according to the Preparations described below:

endo and exo bicyclo [3.2.1] octan-2-ylamine prepared according to H. Maskill et al., J. Chem. Soc. Perkin II, 1984, 119

NH ₂ a

bicyclo [2.2.2] octan-2-ylamine prepared according to R. Seka et al., Ber. 1942, 1379

NH.

endo and exo bicyclo [3.2.1] octan-3-ylamine prepared according to H. Maskill et al., J. Chem.

Soc. Perkin Trans. II, 1984, 1369

NH.

and nh ₂ endo tricyclo [5.2.1.0 ^2,6 ] decan-8-ylamine prepared according to G. Buchbauer et al., Ar.

Pharm., 1990, 323,336

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NH, endo and exo, 1R and 1S 1,3,3-trimethylbicyclo [2.2.1] heptan-2-ylamine prepared according to Ingersoll et al., J. Am. Chem. Soc., 1951, 73, 3360 or according to J. A. Suchocki et al., J. Med. Chem., 1991, 34, 1003-1010:

h ₂ n ch ₃

3-methylcyclohexylamine prepared according to Smith et al., J. Org. Chem., 1952, 17,294:

ch ₃

2,6-dimethylcyclohexylamine prepared according to Cornubert et al., Bull. Soc. Chim. Fr., 1945, 12, 367

2-methoxycyclohexylamine prepared according to Noyce et al., J. Am. Chem. Soc. 1954, 76, 768:

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4-ethylcyclohexylamine prepared according to A. Shirahat et al., Biochem. Pharmacol.

1991,41,205:

bicyclo [2.2.2] oct-2-en-5-amine prepared according to H. L. Goering et al., J. Am. Chem. Soc., 1961, 83, 1391

N-ethyl-1-adamantylamine prepared according to V. L. Narayanan et al., J. Med. Chem., 1972, 15, 433:

NHCH ₂ CH ₃ tricyclo [2.2.1.0 ^{2 '6]} heptan-3-ylamine prepared according to G. Muller et al., Chem. Ber., 1965, 98, 1097

N-methyl-exo-bicyclo [2.2.1] heptan-2-ylamine prepared according to W. G. Kabalk et al.,

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2,2,6,6-tetramethylcyclohexylamine prepared according to J. Chem, Soc., C, 1970, 1845:

The alcohols of the formula HO-R ₂ are either commercially available or described in the literature or prepared by known methods. For example, it is possible to carry out the reduction of the corresponding ketones to obtain alcohols of formula (XIV). The reduction takes place by means of a reducing agent such as sodium borohydride in a solvent such as methanol or aluminum hydride and lithium in a solvent such as tetrahydrofuran or diethyl ether at a temperature between ambient temperature and the reflux temperature of the solvent.

In particular, it is possible to prepare 2,2,6,6-tetramethylcyclohexanol according to the Compendium Hebdomadaire des Séance de Académie des Science, 156, 1201.

Use of compounds of formula (III) in enantiomerically pure form in step 1 of method A or use of compounds of formula (XIV) in enantiomerically pure form in step 1 of method B and use of compounds of formula (VII) or (VIII) in enantiomerically pure stages of a di and ei of scheme 1 or step e of scheme ₃ 3 Compounds of formula (II) allows to obtain a compound of formula (I) in enantiomerically pure form.

The resolution of the racemic mixtures of compounds of formula (III), (VII), (VIII) or (XIV) is carried out by methods well known to those skilled in the art.

The compounds of formula (I) show very good affinity in vitro for CB ₂ receptors under the experimental conditions described by Bouaboula et al., Eur. J. Biochem., 1993, 214, 173-180.

The compounds of the present invention and their possible salts are particularly potent and selective CB ₂ receptor ligands having a Ki generally in the range of between 0.1 and

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100 nM. They are generally from 10 to 1000 times more active against CB ₂ receptors than against CB 1 receptors and are effective when administered orally.

The compounds (I) of the invention are CB ₂ receptor antagonists. The antagonist effect of these compounds against CB ₂ receptors has been determined in various models. Cannabinoid receptor agonists ( ^{9 9} -THC, WIN 55212-2, or CP 55940) are known to be able to inhibit Forskolin-induced adenylate cyclase activity, as described in M. Rinaldi - Carmona et al., Journal of Pharmacology and Experimental Therapeutics, 1996 , 278, 871-878. In this model, compounds (I) of the invention are able to completely block the effect of cannabinoid receptor agonists.

On the other hand, cannabinoid receptor agonists (WIN 55212-2 or CP-55940) at nanomolar concentrations are known to increase the proportion of DNA synthesis of human B cells co-stimulated with anti-Ig antibodies: an increase in thymidine incorporation of about 40% (JM Derocq et al. , FEBS Letters, 1995, 369, 177-182). When the compounds (I) of the invention or their possible salts are used in a wide range of concentrations from 10 ^-1 M to 10 ^-6 M, they are observed to block the agonist-induced increase in DNA synthesis of human B cells (stimulated as described above). cannabinoid receptors (WIN 55212-2 or CP 55940).

In addition, cannabinoid receptor agonists (CP 55940 or WIN 552122) induce activation of mitogen activated protein kinases (MAPKs) in cells expressing the CB ₂ receptor. The compounds (I) of the invention specifically block this MAPK activation induced by cannabinoid receptor agonists (CP 55940 or WIN 55212-2).

The compounds of the invention, or their possible salts, also exhibit affinity in vivo for the CB ₂ cannabinoid receptors present in the spleen of mice when administered by the intravenous, intraperitoneal or oral route. Their activity was demonstrated by ex vivo binding experiments with [ ³ H] -CP 55940. The experiments were performed under the conditions described in M. Rinaldi - Carmona et al., Life Science, 1995, 56, 1941 - 1947.

The compounds of the present invention have toxicity that is compatible with their use as a medicament. Due to their remarkable properties, in particular due to their high affinity and their selectivity for peripheral CB ₂ receptors, the compounds may be

3 ·. ' 983 / H of formula (I), either alone or in the form of their pharmaceutically acceptable salts, used as active ingredient of medicaments.

The diseases for which Compound (I) or a pharmaceutically acceptable salt thereof may be used are diseases related to immune system cells and immune disorders such as autoimmune diseases, organ transplant diseases, infectious diseases, allergic diseases, gastrointestinal diseases such as Crohn's disease. Particular mention may be made of the following autoimmune diseases: diffuse lupus erythematosus, conjunctival disease, Sjögren's syndrome, immobilizing spondylartritis, reactive arthritis, rheumatoid polyarthritis, undifferentiated spondylartritis, psoriasis haemorrhoea, psoriasis disease, anesthesia disease, anesthesia disease. Allergic diseases that can be treated can be, for example, of the type of direct hypersensibility or asthma. Likewise, the compounds of the invention and their possible pharmaceutically acceptable salts can be used to treat vascularities, parasitic infections, viral infections, bacterial infections, amylases, diseases affecting the lymphohematous system lines.

Accordingly, a further object of the present invention is a method of treating the above-mentioned diseases, comprising administering to a patient in need thereof an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof.

A further object of the present invention is also the use of the compounds of formula (I) for the preparation of medicaments for the treatment of CB2 cannabinoid receptor related disorders, in particular related to immune disorders and / or diseases related to the immune system.

In addition, compounds (I) or (XIII) of the invention, either alone or radiolabelled, can be used as pharmacological tools for the detection and labeling of peripheral CB2 cannabinoid receptors in humans and animals. This use is a further object of the present invention.

The compounds of the present invention are generally administered in unit doses. Said unit doses are preferably formulated as pharmaceutical compositions in which the active ingredient is mixed with a pharmaceutical excipient.

3G983 / H

Accordingly, a further object of the present invention are pharmaceutical compositions comprising as an active ingredient a compound of formula (I) or one of its pharmaceutically acceptable salts.

The compounds of formula (I) described above and their pharmaceutically acceptable salts can be used at daily dosages of from 0.01 to 100 mg per kilogram of body weight of the mammal to be treated, preferably at daily dosages of from 0.1 to 50 mg / kg. In humans, the dosage may vary preferably from 0.5 to 4000 mg per day, more preferably from 2.5 to 1000 mg, depending on the age of the subject being treated and / or the type of treatment, prevention or treatment.

In the pharmaceutical compositions of the present invention intended for administration by the oral, sublingual, inhalation, subcutaneous, intramuscular, intravenous, transdermal, topical or rectal routes, the active ingredients may be administered in unit form, mixed with conventional pharmaceutical carriers. both animals and humans. Suitable unit dosage forms include, for oral administration, tablets, gelatin capsules, powders, granules and solutions or oral suspensions, sublingual and buccal administration, aerosols, implants, subcutaneous, intramuscular, intravenous, intranasal or intraocular, and rectal forms. .

If the composition is prepared as a solid in the form of a tablet, a wetting agent such as sodium lauryl sulfate may be added to the active ingredient, which may or may not be micronized, and mixed with a pharmaceutical vehicle such as silica, gelatin, starch, lactose, magnesium stearate, talc, acacia or analogues. It is possible to give the tablets a coating of sucrose, various polymers or other suitable substances, or additionally modify them to have a prolonged or delayed effect and to release in a continuous manner a preselected amount of the active ingredient.

Gelatin capsules are obtained by mixing the active ingredient with a diluent such as glycol or glycerol ester and incorporating the resulting mixture into soft or hard capsules.

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A preparation in the form of a syrup or elixir may contain the active ingredient together with a sweetening agent, preferably non-caloric, methyl paraben and propyl paraben as antiseptics, as well as an agent giving a suitable taste and color.

Water-soluble powders or granules may contain the active ingredient in admixture with dispersing agents, wetting agents or suspending agents such as polyvinylpyrrolidone and further with sweetening or flavoring agents.

For rectal administration, suppositories that are formulated with binders that melt at rectal temperature, such as cocoa butter or polyethylene glycols, are used.

Aqueous suspensions, saline isotonic solutions or sterile and injectable solutions containing pharmacologically acceptable dispersing agents and / or pharmacologically acceptable solubilizing agents, for example propylene glycol or polyethylene glycol, are used for parenteral, intranasal or intracocular administration.

A co-solvent may be used to prepare an aqueous injectable solution for intravenous administration: an alcohol such as ethanol, a glycol such as polyethylene glycol or propylene glycol, and a hydrophilic surfactant such as Tween® 80. For the preparation of an oily solution injectable by intramuscular route, the active ingredient or triglyceride an ester of glycerol.

Creams, ointments and gels may be used for topical administration.

For transdermal administration, multilaminated patches or reservoir patches may be used in which the active ingredient may be in an alcoholic solution.

For administration by inhalation, an aerosol containing, for example, sorbitan trioleate or oleic acid as well as trichlorofluoromethane, dichlorofluoromethane, dichlorotetrafluoroethane or any other propellant that is biocompatible is used; it is also possible to use a system comprising the active ingredient alone or associated with an excipient in powder form.

The active ingredient may also be formulated in the form of microcapsules or microspheres, optionally with one or more carriers or additives.

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The active ingredient may also be presented in the form of a complex with a cyclodextrin, for example alpha-, beta- or gamma-cyclodextrin, 2-hydroxypropyl-beta-cyclodextrin or methyl-beta-cyclodextrin.

Implants may be used as sustained release forms of the active ingredient in the treatment of chronic diseases. These may be prepared in the form of oily suspensions or in the form of suspensions of microspheres in an isotonic environment.

In each unit dose, the active compound of formula (I) is present in an amount adapted to the desired daily dose.

In general, each unit dose is preferably adjusted according to the dosage and the intended mode of administration, for example in tablets, gelatin capsules and the like, sachets, ampoules, syrups and the like, drops such that each unit dose contains from 0.5 to 1000 mg of the active ingredient, preferably from 2.5 to 250 mg, which is administered one to four times a day.

DETAILED DESCRIPTION OF THE INVENTION

The following examples illustrate the invention without limiting it in any way.

Melting points or decomposition products, F, are measured in a capillary tube or a Tottoli instrument.

Proton NMR spectra are recorded at 200 MHz in DMSO-d ₆ .

The equipment used for preparative HPLC is a Prochrom LC 50 model with a column diameter of 50 mm and a maximum bed height ranging from 35 to 40 cm.

The conditions used are:

• Stationary phase: Kromasil C 18 - 100 A10 μ • Mobile phase:

Washing solvent A: H ₂ O

Washing solvent B:

methanol / H ₂ O (90/10 by volume) • Flow rate: 114 ml / min; pump position 8 mm.

30983 / H • elution gradient:

Time (mn) % A % B 0 10 90 5 10 90 5 10 90

• UV detection at λ = 230 nm

Cell length ... 0

Dilution = 0.5 AUFS

The apparatus used for analogous HPLC is a Hewlett Packard HPLC instrument. The conditions used are:

® Column: stationary phase: Kromasil (Waters)

C 18-100 A 10 pm • Mobile phase:

Washing solvent A: H ₂ O

Elution solvent: methanol • Elution gradient:

Time (mn) % A % B 0 20 80 5 20 80 20 7 93

• Flow rate: 1 ml / mn • Detection: UV λ = 230 nm, dilution = 8 • Injection volume: 30 μΙ.

The following abbreviations are used in the Preparations and Examples:

Me, OMe: methyl, methoxy

Et, OEt: ethyl, ethoxy

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EtOH: ethanol

MeOH: methanol

Ether: diethyl ether

Isoether: diisopropyl ether

DMF: dimethylformamide

DMSO: dimethylsulfoxide

DCM: dichloromethane

CCI ₄ : carbon tetrachloride

THF: tetrahydrofuran

AcOEt: ethyl acetate

K ₂ CO ₃ : potassium carbonate

Na ₂ CO 3: sodium carbonate

KHCO3: potassium bicarbonate

NaHCO 3: sodium bicarbonate

NaCl: sodium chloride

Na ₂ SO ₄ : sodium sulphate

MgSO ₄ : magnesium sulfate

NaOH: sodium hydroxide

KOH: potassium hydroxide

AcOH: acetic acid

H ₂ SO ₄ : sulfuric acid

HCl: hydrochloric acid

HBr: hydrobromic acid hydrochloric ether: a saturated solution of hydrochloric acid in ether

BOP: benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate

DBU: 1,8-diazabicyclo [5.4.0] undec-7-ene

30J83 / H

NH ₄ Cl: ammonium chloride

F: melting point

Eb: boiling point

TA: ambient temperature silica H: silica gel 60H sold by Merck (Darmstadt)

HPLC: high performance liquid chromatography

TR: retention time

NMR: nuclear magnetic resonance delta: chemical displacement expressed in parts per million s: singlet se: extended singlet sd: doubled singlet d: doublet dd: doubled doublet t: triplet qd: quadruplet sept: septuplet mt: multiplet m: massif.

Preparations

Preparation 1.1

1- (3,4-Dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid

A. Methyl 4- (4-methylphenyl) -2-oxo-4-oxydobut-3-enate sodium salt

6.24 g of sodium are dissolved in 150 ml of methanol. After cooling to ambient temperature was added

36.4 ml of 4'-methylacetophenone and then a solution of 37 ml of diethyl oxalate in 50 ml of methanol.

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Methanol (100 ml) was then added to fluidize the reaction mixture and allowed to stir at ambient temperature for 2 hours. Ether (500 ml) was added and allowed to stir at ambient temperature for 30 minutes. The precipitate formed is drained, washed in ether and dried. 57.4 g of the expected product are obtained.

B. 5- (4-Methylphenyl) pyrazole-3-carboxylic acid methyl ester

A mixture of 30 g of the compound obtained in the previous stage in 100 ml of AcOH is cooled in an ice bath and 7.94 ml of a 55% hydrazine solution in water are added dropwise. The reaction mixture was then heated to reflux for 5 hours and left stirring at room temperature overnight. The precipitate formed is drained, washed with water and the first batch is obtained. The filtrate is poured into water / ice, the precipitate formed is drained, washed with water, dried and a second crop is obtained. The first and second batches were combined, washed with AcOEt, and dried under vacuum. 21.44 g of the expected product are obtained.

C. 1- (3,4-Dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid methyl ester

To a suspension of 5 g of the compound obtained in the preceding step in 50 ml of toluene, 2.03 g of sodium hydride 60% in oil are added in portions and then the reaction mixture is heated to 65 ° C for 1 hour. After cooling to ambient temperature, 5.82 g of 3,4-dichlorobenzyl bromide was added dropwise and then heated to reflux for 20 hours. The reaction mixture was cooled to ambient temperature and 100 mL of a 50% NH 4 Cl solution in water was added dropwise. After decantation, the organic phase is washed with saturated NaCl solution, dried over _MgSO4 and the solvent removed in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (75/25, v / v). 5.28 g of the expected product are obtained, m.p. = 98.6 ° C.

D. 1- (3,4-Dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid

To a solution of 5.2 g of the compound obtained in the previous step in 100 ml of EtOH is added at ambient temperature a solution of 1.16 g of KOH in 20 ml of water and then heated to reflux for 5 hours. The reaction mixture was allowed to stir overnight, 200 mL of aqueous HCl N was added at ambient temperature, the precipitate formed was drained and dried under vacuum. 5.12 g of the expected product are obtained, m.p. = 171.5 ° C.

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NMR: .delta. (Ppm): 2.4, s, 3H, 5.5, s, 2H, 6.9, s, 1H, 7.0, dd, 1H, 7.3, d, 1H, 7.35 AA '- BB' system: 4H, 7.65, d, 1H, 13.0, sc, 1H.

An Overhauser effect (NOE) between the benzyl protons _(R4 = _R5 = H) and the protons _g2 = g6 = H

Preparation 1.2

1- (3-Chloro-4-methylbenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid

1- (3-Chloro-4-methylbenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Step C of Preparation 1.1, starting from 5 g of the compound obtained in Step B of Preparation 1.1, 2.03 g of sodium hydride 60% in oil, 100 ml of toluene and 4.22 g of 3-chloro-4- chloride. methylbenzyl. 1.52 g of the expected product are obtained.

B. 1- (3-Chloro-4-methylbenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid

To a solution of 1.52 g of the compound obtained in the previous step in 50 ml of EtOH was added at room temperature a solution of 0.36 g of KOH in 10 ml of water and then heated to reflux for one night. The reaction mixture is concentrated in vacuo, the residue is taken up with water, the aqueous phase is washed with ether, the aqueous phase is acidified to pH = 2 by addition of HCl 6N solution, the precipitate formed is drained, washed with water and dried under vacuum. 1.42 g of the expected product are obtained, m.p. = 108.5 ° C.

NMR: .delta. (Ppm): 2.1 to 2.45, 2s, 6H, 5.4, s, 2H, 6.7 to 7.5, m, 8H, 12.85, s, 1H.

Preparation 1.3

1- (3-Fluoro-4-methylbenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid and 1- (3-Fluoro-4-methylbenzyl) -3- (4-methylphenyl) pyrazole-5-carboxylic acid

A. 1- (3-Fluoro-4-methylbenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid methyl ester and 1- (3-Fluoro-4-methylbenzyl) -3- (4-methylphenyl) pyrazole- methyl ester

5-carboxylic acid

To a suspension of 2.5 g of the compound obtained in Stage B of Preparation 1.1 in 100 ml of toluene, 1.01 g of sodium hydride 60% in oil are added in portions and then the reaction mixture is heated at 65 ° C for 1 hour. . After cooling to ambient temperature, 2.45 g of 3-fluoro-4-methylbenzyl bromide (Preparation 3.1) is added dropwise and

30983 / H, then the mixture was heated to reflux for 48 hours. After cooling to ambient temperature, 50 ml of a 50% NH ₄ Cl solution in water are added dropwise. After decantation, the organic phase is washed with saturated NaCl solution, dried over _MgSO4 and the solvent removed in vacuo. The residue is chromatographed on silica gel eluting with AcOEt / cyclohexane (50/50, v / v). 1.29 g of a mixture of the expected products are obtained.

B. 1- (3-Fluoro-4-methylbenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid 1- (3-fluoro-4-methylbenzyl) -3- (4-methylphenyl) pyrazole-5 carboxylic acid

To a solution of 1.2 g of a mixture of the compounds obtained in the previous step in 50 ml of EtOH, a solution of 0.3 g of KOH in 10 ml of water is added at ambient temperature, and then the mixture is refluxed for 5 hours and left overnight stirring at ambient temperature. The reaction mixture is concentrated under vacuum, the residue is taken up with water, the aqueous phase is washed with AcOEt, then the aqueous phase is acidified to pH = 2 by addition of HCl 6N solution, the precipitate formed is drained, washed with water and dried under vacuum. 0.95 g of a mixture of the expected products is obtained.

Preparation 1.4

A. Methyl 4- (4-methoxyphenyl) -2-oxo-4-oxydobut-3-enate sodium

3.9 g of sodium are dissolved in 100 ml of methanol. After cooling to ambient temperature was added

25.4 g of 4'-methoxyacetophenone and then a solution of 23 ml of diethyl oxalate in 50 ml of methanol are left under stirring at room temperature for 2 hours. Ether (500 ml) was added and allowed to stir at ambient temperature for 30 minutes. The precipitate formed is drained, washed in ether and dried. 33.4 g of the expected product are obtained.

B. 5- (4-Methoxyphenyl) pyrazole-3-carboxylic acid methyl ester

A mixture of 9 g of the compound obtained in the previous step in 100 ml of AcOH is cooled in an ice bath and 2.2 ml of hydrazine monohydrate is added dropwise. The reaction mixture was then heated to reflux for 5 hours and left stirring at room temperature overnight. The reaction mixture is poured onto a water / ice mixture, the precipitate formed is drained and washed with water. The precipitate was vyoerie in dichloromethane, the insoluble material was filtered, the filtrate was dried over MgSO () ₄ and the solvent evaporated in vacuo. 7.1 g of the expected product are obtained.

3C983 / H

C. 1- (3,4-Dichlorobenzyl) -5- (4-methoxyphenyl) pyrazole-3-carboxylic acid methyl ester

This compound is prepared as described in Step C of Preparation 1.1, starting from 3.5 g of the compound obtained in the previous step, 1.32 g of 60% sodium hydride in oil, 150 ml of toluene and 3.77 g of 3,4- dichlorobenzyl. The product is chromatographed on silica gel eluting with cyclohexane / AcOEt (60/40, v / v). 2.4 g of the expected product are obtained, m.p. = 95.5 ° C.

NMR: .delta. (Ppm): 3.8, 2s, 6H, 5.45, s, 2H, 6.8-7.1, m, 4H, 7.25, d, 1H, 7.35, d, 2H 7.55, d, 1H.

D. 1- (3,4-Dichlorobenzyl) -5- (4-methoxyphenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.2, starting from 2.4 g of the compound obtained in the previous step, 50 ml EtOH, 0.51 g KOH and 10 ml water. 2.23 g of the expected product are obtained.

Preparation 1.5

1- (3-Chloro-4-methylbenzyl) -5- (4-methoxyphenyl) pyrazole-3-carboxylic acid 1- (3-chloro-4-methylbenzyl) -3- (4-methoxyphenyl) pyrazole-5-carboxylic acid

A. 1- (3-Chloro-4-methylbenzyl) -5- (4-methoxyphenyl) pyrazole-3-carboxylic acid methyl ester and 1- (3-Chloro-4-methylbenzyl) -3- (4-methoxyphenyl) pyrazole-5- methyl ester carboxylic acid

A mixture of the two compounds is prepared as described in Step A of the Preparation

1.3, starting from 3.5 g of the compound obtained in Preparation B of Preparation 1.4, 1.32 g of sodium hydride 60% in oil, 100 ml of toluene and 2.75 g of 3-chloro-4-methylbenzyl chloride. 1.93 g of a mixture of the expected products are obtained.

B. 1- (3-Chloro-4-methylbenzyl) -5- (4-methoxyphenyl) pyrazole-3-carboxylic acid 1- (3-chloro-4-methylbenzyl) -3- (4-methoxyphenyl) pyrazole-5 carboxylic acid

A mixture of the two compounds is prepared as described in Step B of the Preparation

1.3, starting from 1.9 g of a mixture of the compounds obtained in the previous stage, 50 ml of EtOH, 0.43 g of KOH and 10 ml of water. 1.73 g of a mixture of the expected products are obtained.

3C983 / H

Preparation 1.6

1- (3-Chloro-4-methylbenzyl) -5- (4-fluorophenyl) pyrazole-3-carboxylic acid

A. Methyl 4- (4-fluorophenyl) -2-oxo-4-oxydobut-3-enate sodium salt

This compound was prepared as described in Step A of Preparation 1.1 starting from 4.16 g of sodium in 100 mL of methanol, 21.87 mL of 4'-fluoroacetophenone and 24.72 mL of diethyl oxalate in 50 mL of methanol. 42.68 g of the expected product are obtained.

B. 5- (4-Fluorophenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in step B of Preparation 1.1, starting from 15 g of the compound obtained in the previous step, 100 ml of AcOH and 3.73 ml of a 55% solution of hydrazine in water. After stirring overnight at room temperature, the reaction mixture is poured into water / ice, the precipitate formed is drained, washed with water and dried. 10.74 g of the expected product are obtained.

C. 1- (3-Chloro-4-methylbenzyl) -5- (4-fluorophenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Step C of Preparation 1.1, starting with 3.5 g of the compound obtained in the previous step, 1.4 g of sodium hydride 60% oil, 100 ml of toluene and 4.45 g of 3-chloro-4 iodide. -methylbenzyl (Preparation 3.2) in 50 ml toluene. Chromatograph on silica gel eluting with cyclohexane / AcOEt (70/30, v / v). 1.57 g of the expected product are obtained, m.p. = 110 ° C.

D. 1- (3-Chloro-4-methylbenzyl) -5- (4-fluorophenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.2, starting from 1.55 g of the compound obtained in the previous step, 50 ml of EtOH, 0.36 g of KOH and 10 ml of water. 1.46 g of the expected product are obtained, m.p. = 120 ° C.

Preparation 1.7

1- (2,4-Dichlorobenzyl) -5- (4-chlorophenyl) pyrazole-3-carboxylic acid

A. Methyl 4- (4-chlorophenyl) -2-oxo-4-oxydobut-3-enate sodium salt (983 / H)

This compound was prepared as described in Step A of Preparation 1.1 starting from 12.66 g of sodium in 270 ml of methanol, 68.4 ml of 4'-chloroacetophenone and 71.8 ml of diethyl oxalate in 110 ml of methanol. 97 g of the expected product are obtained.

B. 5- (4-Chloro-phenyl) -pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Step B of Preparation 1.4, starting from 15 g of the compound obtained in the previous step, 65 ml of AcOH, 3.05 ml of hydrazine monohydrate. The precipitate obtained is triturated in a mixture of 100 ml of dichloromethane and 50 ml of AcOEt, the substance is drained and dried. 8.13 g of the expected product are obtained, m.p. = 215 ° C.

C. 1- (2,4-Dichlorobenzyl) -5- (4-chlorophenyl) pyrazole-3-carboxylic acid methyl ester

To a suspension of 1.02 g of sodium hydride 60% in oil, in 100 ml of toluene, a solution of 5.07 g of the compound obtained in the previous stage in 100 ml of toluene is added dropwise at ambient temperature and then the mixture is heated to 65 ° C. for 1 hour. 3.12 ml of 2,4-dichlorobenzyl chloride are then added and the mixture is heated to reflux for 20 hours. The reaction mixture was cooled to ambient temperature and 100 mL of a 50% NH ₄ Cl solution in water was added. After decantation, the organic phase is washed with saturated NaCl solution, dried over _MgSO4 and the solvent removed in vacuo. The residue is chromatographed on silica gel, eluting with toluene / dichloromethane / AcOEt (80/10/10 by volume). 3.68 g of the expected product are obtained, m.p. = 105 ° C.

D. 1- (2,4-Dichlorobenzyl) -5- (4-chlorophenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step D of Preparation 1.1, starting from 3.6 g of the compound obtained in the previous step, 60 ml of methanol, 1.27 g of KOH and 6 ml of water. 3.52 g of the expected product are obtained, m.p. = 185 ° C.

Preparation 1.8

1- (3-Chloro-4-methylbenzyl) -5- (3,4-dimethylphenyl) pyrazole-3-carboxylic acid

A. Methyl 4- (3,4-dimethylphenyl) -2-oxo-4-oxydobut-3-enate sodium

30983 / H

This compound was prepared as described in Stage A of Preparation 1.1 starting from 3.9 g of sodium in 100 ml of methanol, 25 g of 3 ', 4'-dimethylacetophenone and 23 ml of diethyl oxalate in 50 ml of methanol. 39.42 g of the expected product are obtained.

B. 5- (3,4-Dimethyl-phenyl) -pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Step B of Preparation 1.6, starting from 10 g of the compound obtained in the previous step in 150 ml of AcOH and

2.2 ml of a 55% hydrazine solution in water. 9 g of the expected product are obtained.

C. 1- (3-Chloro-4-methylbenzyl) -5- (3,4-dimethylphenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Step C of Preparation 1.1, starting from 1.52 g of 60% sodium hydride, 4 g of the compound obtained in the previous step, 70 ml of toluene and 5.8 g of 3-chloro-4-methylbenzyl iodide. (Preparation 3.2). The product obtained is purified by trituration in hexane and then dried and washed in hexane. 2.84 g of the expected product are obtained, m.p. = 88 ° C.

NMR: .delta. (Ppm): 2.0-2.35, m, 9H, 3.95, s, 3H, 5.3, s, 2H, 6.6-7.4, m, 7H.

D. 1- (3-Chloro-4-methylbenzyl) -5- (3,4-dimethylphenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.2, starting from 1.8 g of the compound obtained in the previous step in 30 ml of EtOH and 0.392 g of KOH in 30 ml of water. 1.6 g of the expected product are obtained, m.p. = 163 ° C.

Preparation 1.9

1- (3-Chloro-4-fluorobenzyl) -5- (3,4-dimethylphenyl) pyrazole-3-carboxylic acid

A. 1- (3-Chloro-4-fluorobenzyl) -5- (3,4-dimethylphenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Stage C of Preparation 1.1 starting from 2.5 g of the compound obtained in Stage B of Preparation 1.8, 50 mL of toluene, 88 g of sodium hydride 60% in oil, and 2.5 g of 3-chloro- Of 4-fluorobenzyl bromide (Preparation 3.3).

30983 / H

The product is purified by trituration in AcOEt and then dehydrated and dried. 3.6 g of the expected product are obtained.

B. 1- (3-Chloro-4-fluorobenzyl) -5- (3,4-dimethylphenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.2, starting from 1.6 g of the compound obtained in the previous step in 25 ml of EtOH and 0.481 g of KOH in 10 ml of water. 1.22 g of the expected product are obtained. NMR: .delta. (Ppm): 2.2, 2s, 6H, 5.35, s, 2H, 6.6-7.4, m, 7H.

Preparation 1.10

1- (4-Methylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

A. Methyl 4- (4-chloro-3-methylphenyl) -2-oxo-4-oxy-but-3-enate sodium salt

This compound was prepared as described in Step A of Preparation 1.1 starting from 7.6 g of sodium in 100 ml of methanol, 55.6 g of 4'-chloro-3'-methylacetophenone and 45 ml of diethyl oxalate in 100 ml of methanol. 85.8 g of the expected product are obtained.

B. 5- (4-Chloro-3-methyl-phenyl) -pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Step B of Preparation 1.4, starting from 15 g of the compound obtained in the previous step in 150 ml of AcOH and 2.9 ml of hydrazine monohydrate. After stirring overnight at room temperature, the reaction mixture is poured into ice water, the precipitate formed is drained and washed with water. 13 g of the expected product are obtained after drying.

C. 1- (4-Methylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Stage C of Preparation 1.1 starting from 5 g of the compound obtained in the previous stage in 50 ml of toluene, 1.8 g of sodium hydride 60% in oil and 4.07 g of 4-methylbenzyl bromide. 4.6 g of the expected product are obtained, m.p. = 98 ° C.

NMR: .delta. (Ppm): 2.0 to 2.4, 2s, 6H, 3.8, s, 3H, 5.4, s, 2H, 6.7 to 7.6, m, 8H.

D. 1- (4-Methylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

3C983 / H

This compound was prepared as described in Step B of Preparation 1.2, starting from 4 g of the compound obtained in the previous step in 100 ml of EtOH and 0.95 g of KOH in 20 ml of water. 3.4 g of the expected product are obtained, m.p. = 180 ° C.

NMR: .delta. (Ppm): 2.25, s, 3H, 2.35, s, 3H, 5.4, s, 2H, 6.7-7.15, m, 5H, 7.25, dd, 1H 7.4 to 7.6, m, 2H.

Following the procedures described in stage C (starting from compound 10 obtained in stage B of Preparation 1.10 and the halides of the appropriate benzyls) and then in stage D of Preparation 1.10, the esters and then the acids described in the following Table are prepared.

First

preparation w ₃ w ₄ 1.11 H F 1.12 Cl Me 1.13 Cl F

Preparation 1.11: Z = OMe.

NMR: .delta. (Ppm): 2.35, s, 3H, 3.85, s, 3H, 5.5, s, 2H, 6.8-7.6, m, 8H.

Preparation 1.14

1- [1- (2,4-Dichlorophenyl) ethyl] -5- (4-chlorophenyl) pyrazole-3-carboxylic acid

3C983 / H

A. 1- [1- (2,4-Dichlorophenyl) ethyl] -5- (4-chlorophenyl) pyrazole-3-carboxylic acid methyl ester i

To a suspension of 1.5 g of the compound obtained in Preparation B of Preparation 1.7 in 50 ml of toluene is added at ambient temperature and in portions 0.3 g of sodium hydride 60% in oil, and then the mixture is heated at 65 ° C for 30 minutes. . After cooling to ambient temperature, 1.77 g of 1- (1-bromomethyl) -2,4-dichlorobenzene (Preparation 3.4) was added dropwise and then the mixture was heated to reflux for 5 days. After cooling to ambient temperature, the reaction mixture is poured onto 100 ml of a 50% NH ₄ Cl solution in water cooled to 0 ° C. Extract in AcOEt, wash the organic phase with water, saturated NaCl solution, dry over MgSO ₄ and evaporate the solvent in vacuo. The residue is chromatographed on silica gel, eluting with toluene / AcOEt (95/5, v / v). 1.02 g of the expected product is obtained.

B. 1- [1- (2,4-Dichlorophenyl) ethyl] -5- (4-chlorophenyl) pyrazole-3-carboxylic acid

To a solution of 1.02 g of the compound obtained in the previous step in 20 ml of methanol is added at ambient temperature a solution of 0.35 g of KOH in 5 ml of water, and then the mixture is refluxed for 2 hours. The reaction mixture is poured into 100 ml of a 5% HCl solution cooled to 0 ° C, the precipitate formed is drained, washed with water and dried under vacuum. 0.74 g of the expected product is obtained, m.p. = 80 ° C.

Preparation 1.15

1- (3,4-Dichlorobenzyl) -5- (2,6-dimethoxyphenyl) pyrazole-3-carboxylic acid

A. Ethyl 4- (2,6-dimethoxyphenyl) -2-oxo-4-oxydobut-3-enate potassium salt

A mixture of 18 g of 2 ', 6'-dimethoxyacetophenone in 54 ml of EtOH is heated to 50 ° C and a solution of 13.4 g of potassium tert-butylate in 72 ml of EtOH is added over 5 minutes. The reaction mixture is heated to reflux and 16.3 ml of diethyl oxalate are added over 10 minutes and heating is continued at reflux for 1 hour. Distilled with 40 ml of EtOH and then allowed to stir for 2 hours 30 minutes while allowing the temperature to drop to ambient temperature, the precipitate formed was drained, washed with EtOH and dried in vacuo at 6 ° C. 31 g of the expected product are obtained.

B. 5- (2,6-Dimethoxyphenyl) pyrazole-3-carboxylic acid methyl ester

30983 / H

This compound was prepared as described in Step B of Preparation 1.4, starting with 4 g of the compound obtained in the previous step, 50 ml of AcOH and 0.7 ml of hydrazine monohydrate. After stirring overnight at room temperature, the reaction mixture is poured onto water / ice, extracted with AcOEt, the organic phase is washed with saturated NaCl solution, dried over Na ₂ SO ₄ and the solvent is partially concentrated in vacuo. The precipitate formed is drained and dried. 2.53 g of the expected product are obtained.

C. 1- (3,4-Dichlorobenzyl) -5- (2,6-dimethoxyphenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step C of Preparation 1.1, starting with 2.5 g of the compound obtained in the previous step, 50 ml of toluene, 0.88 g of sodium hydride 60% in oil and 2.16 g of 3,4-dichlorobenzyl bromide. . After one night at reflux, the reaction mixture is cooled to ambient temperature, 50 ml of a 50% NH ₄ Cl solution in water are added dropwise, the precipitate formed is drained and dried. 1.1 g of the expected product are obtained.

NMR: .delta. (Ppm): 3.5, s, 6H, 4.8, very broad signal, 1H, 4.95, s, 2H, 6.25, s, 1H,

6.6, d, 2H, 6.85, dd, 1H, 6.95, d, 1H, 7.3, t, 1H, 7.4, d, 1H.

Preparation 1.16

1- (4-Fluorobenzyl) -5- (3,4-dimethylphenyl) pyrazole-3-carboxylic acid

A. 1- (4-Fluorobenzyl) -5- (3,4-dimethylphenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Stage C of Preparation 1.1 starting from 2.3 g of the compound obtained in Stage B of Preparation 1.8, 50 mL of toluene, 0.88 g of 60% sodium hydride in oil and 2.08 g of 4-fluorobenzyl bromide. 1 g of the expected product is obtained, m.p. = 93 ° C.

NMR: .delta. (Ppm): 2.25, 2s, 6H, 3.8, s, 3H, 5.4, s, 2H, 6.85, s, 1H, 6.9-7.3, m, 7H .

B. 1- (4-Fluorobenzyl) -5- (3,4-dimethylphenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.14, starting from 1 g of the compound obtained in the previous step, 15 ml of methanol, 0.406 g of KOH and 15 ml of water. 0.94 g of the expected product is obtained, m.p. = 141 ° C.

NMR: .delta. (Ppm): 2.2s, 6H, 3.4, s, 1H, 5.35, s, 2H, 6.75, s, 1H, 6.8-7.3, m, 7H

3G983 / H

Preparation 1.17

1- (2,4-Dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid

A. 1- (2,4-Dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Stage C, Preparation 1.1, starting from 2.5 g of the compound obtained in Stage B of Preparation 1.1, 1 g of sodium hydride 60% in oil, 50 ml of toluene and 2.3 g of chloride 2.4. dichlorobenzyl. 2.53 g of the expected product are obtained, m.p. = 105 ° C.

B. 1- (2,4-Dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid

To a suspension of 1.5 g of the compound obtained in the preceding step in 15 ml of methanol, a solution of 0.5 g of KOH in 15 ml of water is added at ambient temperature, and then the mixture is heated to reflux for 2 hours. The reaction mixture is concentrated under vacuum, the residue is poured onto HCl 1N / ice, the precipitate formed is drained, washed with water and dried under vacuum. 1.4 g of the expected product are obtained.

NMR: .delta. (Ppm): 2.3, s, 3H, 5.45, s, 2H, 6.6-7.7, m, 8H, 12.85, se, 1H.

Preparation 1.18

1- (4-Ethylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

A. 1- (4-Ethylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid methyl ester

This compound is prepared as described in Stage C of Preparation 1.1 starting from 2.5 g of the compound obtained in Stage B of Preparation 1.10 in 50 ml of toluene, 0.88 g of sodium hydride 60% in oil and 2 g of 4-ethylbenzyl bromide (Preparation 3.5). ). After hydrolysis with 50% NH ₄ Cl in water and then decantation, the organic phase is concentrated in vacuo. The residue is extracted with AcOEt, the organic phase is washed with saturated NaCl, dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (80/20, v / v). 2.63 g of the expected product are obtained.

B. 1- (4-Ethylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.17, starting from 2.5 g of the compound obtained in the previous step in 20 ml of methanol and 0.57 g of KOH in 20 ml of water. 2.2 g of the expected product are obtained.

30983 / H

NMR: .delta. (Ppm): 1.1, t, 3H, 2.3, s, 3H, 2.5, mt, 2H, 5.4, s, 2H, 6.7-7.7, m, 8H .

12.9, sc, 1H.

Preparation 1.19

1- (3,4-Dichlorobenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

To a suspension of 2.5 g of the compound obtained in Preparation B, Preparation 1.10 in 25 ml of toluene, was added at room temperature and portionwise 0.88 g of 60% sodium hydride in oil, and then the reaction mixture was heated to 65 ° C for 1 hour. After cooling to ambient temperature, a solution of 2.4 g of 3,4-dichlorobenzyl bromide in 25 ml of toluene is added dropwise and then the mixture is refluxed for one night. The reaction mixture is cooled to ambient temperature, the precipitate formed is drained and dried. 2 g of the expected product are obtained, which product is used as is.

Preparation 1.20

1- (2,4-Dichlorobenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

A. 1- (2,4-Dichlorobenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Step A of Preparation 1.18, starting from 2.5 g of the compound obtained in Step B of Preparation 1.10 in 25 ml of toluene, 0.88 g of sodium hydride 60% in oil and 1.6 ml of 2,4-dichlorobenzyl chloride. in 25 ml of toluene. 0.86 g of product is obtained.

B. 1- (2,4-Dichlorobenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.17, starting from 0.5 g of the compound obtained in the previous step in 15 ml of methanol and 0.205 g of KOH in 15 ml of water. 0.31 g of the expected product is obtained. NMR: .delta. (Ppm): 2.25, s, 3H, 5.4, s, 2H, 6.6-7.6, m, 7H, 3.33, with DOH, 1H.

An Overhauser effect (NOE) between the benzyl protons _(R4 = _R5 = H) and the protons _g2 = g6 = H

Preparation 1.21

1- (4-Methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxylic acid

30983 / H

A. Methyl 4- (3,4-dichlorophenyl) -2-oxo-4-oxydobut-3-enate sodium salt

Dissolve 15.17 g of sodium in 500 ml of methanol. After cooling to ambient temperature, 124.97 g of 3 ', 4'-dichloroacetophenone and then a solution of 91 ml of diethyl oxalate in 400 ml of methanol are added and left to stir at ambient temperature for 2 hours. Add 1 L of ether and leave it to stir at ambient temperature for 30 minutes. The precipitate formed is drained, washed in ether and dried. 140.77 g of the expected product are obtained.

B. 5- (3,4-Dichloro-phenyl) -pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in step B of Preparation 1.1 starting from 15 g of the compound obtained in the previous step in 150 ml of AcOH and 6 ml of a 55% solution of hydrazine in water. After stirring overnight at room temperature, the reaction mixture is poured into ice water, the precipitate formed is drained and washed with water. 12.9 g of the expected product are obtained after drying.

C. 1- (4-Methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxylic acid methyl ester

This compound is prepared as described in Step A of Preparation 1.18, starting from 2.5 g of the compound obtained in the previous step in 25 ml of toluene, 0.88 g of sodium hydride 60% in oil and 1.9 g of 4-methylbenzyl bromide in 25 ml. ml toluene. 0.82 g of the expected product is obtained.

D. 1- (4-Methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.17, starting from 0.7 g of the compound obtained in the previous step in 15 ml of methanol and 0.252 g of KOH in 15 ml of water. 0.65 g of the expected product is obtained.

NMR: .delta. (Ppm): 2.2, s, 3H, 5.35, s, 2H, 6.7-7.2, m, 5H, 7.4, dd, 1H, 7.6-7.8 m, 2H, 12.85, se, 1H.

Preparation 1.22

1- (3-Chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxylic acid

A. 1- (3-Chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxylic acid methyl ester

3C983 / H

This compound was prepared as described in Step A of Preparation 1.18, starting from 20.51 g of the compound obtained in Step B of Preparation 1.21 in 350 mL of toluene, 2.18 g of 60% sodium hydride in oil and 21.96 g.

B. 1- (3-Chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.17, starting from 21.79 g of the compound obtained in the previous step in 50 ml of methanol and 8.93 g of KOH in 50 ml of water. 17.43 g of the expected product are obtained, which product is used as is.

Preparation 1.23

1- (2,4-Dichlorobenzyl) -5- (4-methylthiophenyl) pyrazole-3-carboxylic acid

A. 4'-Methylthioacetophenone

Acetyl chloride (11.8 ml) was added dropwise to a suspension of aluminum chloride (20.4 g) in chloroform (85 ml) at a temperature between 0 ° C and 10 ° C. Then 15 ml of thioanisole are added dropwise at 0-5 ° C and left to stir at ambient temperature for 1 hour 30 minutes. The reaction mixture is cooled to 0 ° C and hydrolyzed by adding 100 ml of water. Extract with chloroform, the organic phase is washed with water, dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. 10.7 g of the expected product are obtained after crystallization in EtOH and recrystallization in heptane.

B. Methyl 4- (4-methylthiophenyl) -2-oxo-4-oxydobut-3-enate sodium salt

1.48 g of sodium are dissolved in 35 ml of methanol and this solution is rapidly added to a suspension of 10.7 g of the compound obtained in the previous step and 9.8 ml of diethyl oxalate in 80 ml of MeOH, cooled to 0 ° C. The mixture was allowed to stir at room temperature for 30 minutes, heated to reflux for 1 hour and then allowed to stir at room temperature for 2 hours. The reaction mixture is poured into 400 ml of ether, left under stirring for 15 minutes, the precipitate formed is drained, washed in ether and dried. 12.8 g of the expected product are obtained.

C. 5- (4-Methyl-thiophenyl) -pyrazole-3-carboxylic acid methyl ester

3C983.TJ

This compound was prepared as described in Step B of Preparation 1.1 starting from 15 g of the compound obtained in the previous step in 140 ml of AcOH and 7 ml of a 5% solution of hydrazine in water. After stirring at room temperature overnight, the reaction mixture is poured into water / ice, the precipitate formed is drained and washed with water. 12.96 g of the expected product are obtained after drying under vacuum and over KOH.

D. 1- (2,4-Dichlorobenzyl) -5- (4-methylthiophenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Step A of Preparation 1.18, starting from 5 g of the compound obtained in the previous step in 100 ml of toluene, 1.063 g of sodium hydride 60% in oil and 3.4 ml of 2,4-dichlorobenzyl chloride. In this way it is obtained

3.2 g of the expected product.

E. 1- (2,4-Dichlorobenzyl) -5- (4-methylthiophenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.14, starting from 1.52 g of the compound obtained in the previous step in 30 ml of methanol and 0.7 g of KOH in 25 ml of water. 1.4 g of the expected product are obtained after drying under vacuum.

NMR: .delta. (Ppm): 2.5, s, 3H, 5.4, s, 2H, 6.6-7.6, m, 8H, 12.8, se, 1H.

Preparation 1.24

1- (2,4-Dichlorobenzyl) -5- (4-trifluoromethylphenyl) pyrazole-3-carboxylic acid

A. Methyl 4- (4-trifluoromethylphenyl) -2-oxo-4-oxydobut-3-enate sodium

This compound was prepared as described in Step A of Preparation 1.4, starting from 4'-trifluoromethyl acetophenone.

B. 5- (4-Trifluoromethylphenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Step C of Preparation 1.23, starting from 6.37 g of the compound obtained in the previous step in 50 ml of AcOH and 3 ml of a 55% solution of hydrazine in water. 5.43 g of the expected product are obtained.

C. 1- (2,4-Dichlorobenzyl) -5- (4-trifluoromethylphenyl) pyrazole-3-carboxylic acid methyl ester

30983 H

This compound was prepared as described in Step A of Preparation 1.18, starting from 2.5 g of the compound obtained in the previous step in 150 ml of toluene, 0.44 g of sodium hydride 60% in oil and 2 ml of 2,4-dichlorobenzyl chloride. 1.82 g of the expected product are obtained.

D. 1- (2,4-Dichlorobenzyl) -5- (4-trifluoromethylphenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.14, starting from 1.6 g of the compound obtained in the previous step in 30 ml of methanol and 0.63 g of KOH in 30 ml of water. 1.5 g of the expected product are obtained.

NMR: .delta. (Ppm): 5.45, s, 2H, 6.85, d, 1H, 6.95, s, 1H, 7.3, dd, 1H, 7.5, d, 1H, 7.55 to 7.8, AA '- BB' system, 4H, 12.9, sc, 1H.

Preparation 1.25

1- [1- (3,4-Dichlorophenyl) ethyl] -5- (4-methylphenyl) pyrazole-3-carboxylic acid

A. 1- [1- (3,4-Dichlorophenyl) ethyl] -5- (4-methylphenyl) pyrazole-3-carboxylic acid methyl ester

To a suspension of 2.5 g of the compound obtained in Preparation B of Preparation 1.1 in 25 ml of toluene is added at ambient temperature and in portions of 1 g of sodium hydride 60% in oil and then heated at 65 ° C for 1 hour. A solution of 3 g of 1- (1-bromomethyl) -3,4-dichlorobenzene (Preparation 3.6) in 25 ml of toluene is then added dropwise and then the mixture is refluxed for one night. Cool to 0 ° C and add dropwise 100 mL of 50% NH ₄ Cl in water. After decantation, the organic phase is washed with saturated NaCl solution, dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (75/25, v / v). 1.6 g of the expected product are obtained.

B. 1- [1- (3,4-Dichlorophenyl) ethyl] -5- (4-methylphenyl) pyrazole-3-carboxylic acid

To a suspension of 1.4 g of the compound obtained in the preceding step in 15 ml of methanol, a solution of 0.5 g of KOH in 15 ml of water was added at ambient temperature, and then the mixture was heated to reflux for 2 hours. After concentration of the methanol in vacuo, the reaction mixture is poured onto HCl 1N / ice, the precipitate formed is drained,

30983 / H was washed with water and dried under vacuum over KOH. 1.25 g of the expected product is obtained.

NMR: .delta. (Ppm): 1.85, d, 3H, 2.4, s, 3H, 5.7, qd, 1H, 6.85, s, 1H, 7.05, dd, 1H, 7.2 to 7.45, m, 5H, 7.65, d, 1H, 12.95, sc, 1H.

Preparation 1.26

1- [1- (4-Methylphenyl) ethyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

A. 1- [1- (4-Methylphenyl) ethyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid methyl ester

This compound was prepared as described in Step A of Preparation 1.25, starting from 2.5 g of the compound obtained in Step B of Preparation 1.10 in 25 ml of toluene, 0.88 g of sodium hydride 60% in oil and 2.3 g of 1- ( 1-bromomethyl) -4-methylbenzene (Preparation 3.7) in 25 ml toluene. After addition of aqueous NH ₄ Cl solution and decantation, the organic phase is concentrated in vacuo, the residue is taken up in AcOEt, washed with saturated NaCl solution, dried over Na ₂ SO ₄ and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (75/25, v / v). 0.7 g of the expected product is obtained.

B. 1- [1- (4-Methylphenyl) ethyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.25, starting from 0.7 g of the compound obtained in the previous step in 15 ml of methanol and a solution of 0.28 g of KOH in 15 ml of water. 0.63 g of the expected product is obtained, which product is used as is.

Preparation 1.27

1- [1- (3,4-Dichloro-phenyl) -ethyl] -5- (4-chloro-3-methyl-phenyl) -pyrazole-3-carboxylic acid

A. 1- [1- (3,4-Dichlorophenyl) ethyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid methyl ester

This compound is prepared as described in Step A of Preparation 1.25, starting from 3.0 g of the compound obtained in Step B of Preparation 1.10 in 25 ml of toluene, 1 g of sodium hydride 60% in oil and 3 g of 1- (1-bromomethyl) - 3,4-Dichlorobenzene (Preparation 3.6) in 25 mL toluene. After addition of aqueous NH ₄ Cl solution and decantation, the organic phase is concentrated under vacuum, the residue is taken up in AcOEt, washed with saturated

30983 / E with NaCl solution, dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (80/20, v / v). 1.4 g of the expected product are obtained.

B. 1- [1- (3,4-Dichlorophenyl) ethyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

This compound was prepared as described in Step B of Preparation 1.25, starting from 1 g of the compound obtained in the previous step in 20 ml of methanol and a solution of 0.40 g of KOH in 20 ml of water. 0.96 g of the expected product is obtained.

NMR: .delta. (Ppm): 1.8, d, 3H, 2.35, s, 3H, 5.7, qd, 1H, 6.7-7.7m, 7H, 12.9, se, 1H.

It is observed Overhauser effect (NOE) between the benzylic proton R ₄ = H, and the protons _g2 = g6 = H

Preparation 1.28

1- [1- (4-Methylphenyl) propyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

A. N, N'-Dipropylidenehydrazine g of propionaldehyde was cooled to 0 ° C, 10 mL of water was added, followed by dropwise addition of 19.9 mL of hydrazine monohydrate keeping the temperature above 10 ° C. Then 67.5 g of KOH in tablets are added in portions and the reaction mixture is allowed to rest overnight at room temperature. After decantation, the organic phase is distilled under reduced pressure. 24.37 g of the expected product are obtained, boiling point = 48 DEG C. at a pressure of 2400 Pa.

B. N-Propylidene-N '- [1- (4-methylphenyl) propyl) hydrazine

100 ml of a 1M solution of 1M ptolylmagnesium bromide in ether are heated to reflux under a nitrogen atmosphere, and then a solution of 10 g of the compound obtained in the previous stage in 40 ml of anhydrous ether is added dropwise and left stirring at room temperature overnight. After cooling the reaction mixture to 5 ° C, saturated aqueous NH ₄ Cl solution was added, decanted, extracted in ether, the combined organic phases were over MgSO ₄ and the solvent was evaporated in vacuo. 6 g of the expected product are obtained, b.p. 102-103 ° C at 20 Pa.

alpha ² % = 1.5180.

3C983'H

C. [1- (4-Methylphenyl) propyl] hydrazine oxalate

To a solution of 4.78 g of oxalic acid in 20 ml of EtOH and 20 ml of ether is added a solution of 6 g of the compound obtained in the previous step in 5 ml of ether and left overnight at 0-5 ° C. The resulting crystallized product is drained and washed in ether. 1.84 g of the expected product are obtained.

D. 1- [1- (4-Methylphenyl) propyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid methyl ester

To a solution of 2 g of the compound obtained in Step A of Preparation 1.10 in 100 ml of water and 100 ml of water. EtOH is added at ambient temperature a solution of 1.84 g of the compound obtained in the previous step in 20 ml of water and 30 ml of EtOH and left under stirring at ambient temperature for 3 hours. The mixture was extracted with ether, the organic phase over Na ₂ SO ₄ 3 solvent removed in vacuo. The residue was taken up in hexane, the insoluble matter was filtered, and the filtrate was concentrated in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (80/20, v / v). 1.12 g of the expected product is obtained.

E. 1- [1- (4-Methylphenyl) propyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

To a solution of 1.1 g of the compound obtained in the preceding step in 40 ml of EtOH is added at ambient temperature a solution of 0.47 g of KOH in 10 ml of water and then heated to reflux for 3 hours. It is concentrated under vacuum, the residue is taken up in 50 ml of water, acidified to pH = 2 by addition of 6N HCl solution, the precipitate formed is drained, washed with water and dried. 0.89 g of the expected product is obtained.

Preparation 1.29

1- [1-Methyl-1- (4-methylphenyl) ethyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

A. N, N'-diisopropylidene hydrazine

This compound was prepared as described in Step A of Preparation 1.28, starting with 92 g of acetone, 20 ml of water, 39.7 ml of hydrazine monohydrate and 135 g of KOH. 66 g of the expected product are obtained, boiling point = 55 DEG C. at 20 mm Hg.

30983 H

B. N-Isopropylidene-N '- [1-methyl-1- (4-methylphenyl) ethyl] hydrazine

100 ml of a solution of 1M p-tolylmagnesium bromide in ether is heated to reflux under a nitrogen atmosphere and then a solution of 8.46 g of the compound obtained in the previous step in 200 ml of anhydrous ether is added dropwise and refluxing is continued for 5 days. . After cooling to 5 ° C, saturated aqueous NH ₄ Cl solution is added, decanted, extracted in ether, the combined organic phases are dried over Na ₂ SO ₄ and the solvent is evaporated off under vacuum. The residue is distilled under reduced pressure. 6.45 g of the expected product are obtained, boiling point = 95 DEG C. at a pressure of 1 mm Hg.

C. [1-Methyl-1- (4-methylphenyl) ethyl] hydrazine oxalate

To a solution of 5.12 g of oxalic acid in 24 mL of EtOH and 24 mL of ether was added a solution

6.45 g of the compound obtained in the previous step in 5 ml of ether were left at room temperature overnight. The resulting crystallized product was drained and washed with hexane. 2.57 g of the expected product are obtained.

D. 1- [1-Methyl-1- (4-methylphenyl) ethyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid methyl ester

To a solution of 2.66 g of the compound obtained in Step A of Preparation 1.10 in 600 ml of water and 1. ¹ EtOH is added at ambient temperature a solution of 2.54 g of the compound obtained in the previous step in 200 ml of water and 300 ml of EtOH and left to stir for 3 hours at ambient temperature and then for 24 hours at rest. The precipitate formed is drained, washed with hexane and dried. 3.46 g of the expected product are obtained.

E. 1- [1-Methyl-1- (4-methylphenyl) ethyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

To a solution of 3.3 g of the compound obtained in the previous step in 80 ml of EtOH, a solution of 1.44 g of KOH in 20 ml of water was added at ambient temperature, and then the mixture was heated to reflux for 3 hours. The insoluble component is filtered and the filtrate is concentrated under vacuum to 20 ml. 30 ml of ice water and 50 ml of dichloromethane, acidified to pH 3.5 by addition of 1 N HCl, decanted, the organic phase over Na ₂ SO ₄ and the solvent evaporated in vacuo. In this way it is obtained

3.15 g of the expected product.

30983 / H

Preparation 1.30

1- (2,4-Dichlorobenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3-carboxylic acid

A. Ethyl 4- (4-chlorophenyl) -3-methyl-4-oxydo-2-oxobut-3-enate lithium salt

154 ml of a solution of 1M lithium hexamethyldisilazane in tetrahydrofuran was added to 120 ml of cyclohexane cooled to 0 ° C under nitrogen. A solution of 21.6 g of 4'-chloropropiophenone in 60 ml of cyclohexane was added dropwise over 30 minutes at 0 ° C and left to stir at room temperature for 3 hours. 21.4 g of diethyl oxalate are then added rapidly, keeping the temperature below 25 ° C and left under stirring at ambient temperature for 48 hours. The resulting precipitate was drained, washed in cyclohexane and dried. 31.3 g of the expected product are obtained.

B. 5- (4-Chloro-phenyl) -4-methyl-pyrazole-3-carboxylic acid ethyl ester

To a solution of 15 g of the compound obtained in the preceding step in 100 ml of AcOH is added dropwise 2.04 ml of hydrazine monohydrate and then heated to reflux for 5 hours and left to stir at room temperature overnight. . The reaction mixture is poured onto water / ice, the precipitate formed is drained, washed with water and then with hexane and dried. 11.47 g of the expected product are obtained.

C. 1- (2,4-Dichlorobenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3-carboxylic acid ethyl ester

To a solution of 2.17 g of the compound obtained in the preceding step in 25 ml of toluene is added at room temperature and in portions 0.72 g of sodium hydride 60% in oil, and then heated at 65 ° C for 1 hour. After cooling to ambient temperature, a solution of 2.28 g of 2,4-dichlorobenzyl chloride in 25 ml of toluene was added dropwise and then heated to reflux for 2 hours. After cooling to ambient temperature, saturated aqueous NH ₄ Cl solution is added, decanted, the organic phase is washed with saturated NaCl solution, dried over MgSO ₄ and the solvent is evaporated off under vacuum. The residue is extracted with AcOEt, the organic phase is washed with saturated NaHCO, buffer solution of pH 2 and with water, dried over _MgSO4 and the solvent removed in vacuo. The residue is chromatographed on silica gel eluting with a mixture

30983}:

cyclohexane / AcOEt (75/25, v / v). 1.10 g of the expected product are obtained, m.p. = 82 ° C.

NMR: .delta. (Ppm): 1.2, t, 3H, 2.0, s, 3H, 4.2, qd, 2H, 5.3, s, 2H, 6.7, d, 1H, 7.15 until

7.6, m, 6H.

An Overhauser effect (NOE) benzyl protons _(R4 = _R5 = H) and the protons _g2 = g6 = H

D. 1- (2,4-Dichlorobenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3-carboxylic acid

To a solution of 0.8 g of the compound obtained in the previous step in 50 ml of EtOH is added at ambient temperature a solution of 0.166 g of KOH in 10 ml of water, then the mixture is heated to reflux for 4 hours. It is concentrated under vacuum, the residue is taken up with water, the insoluble material is filtered, the filtrate is acidified to pH = 2 by addition of HCl 6N, the precipitate formed is drained, washed with water and dried. 0.73 g of the expected product is obtained.

Preparation 1.31

1- (3,4-Dichlorobenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3-carboxylic acid

A. 1- (3,4-Dichlorobenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3-carboxylic acid ethyl ester

This compound was prepared as described in Step C of Preparation 1.30 starting from 2.17 g of the compound obtained in Step B of Preparation 1.30 in 25 mL of toluene, 0.72 g of sodium hydride 60% in oil and 2.99 g of 3,4- dichlorobenzyl bromide, in 25 mL toluene. 1.87 g of the expected product are obtained.

117.5 ° C.

NMR: .delta. (Ppm): 1.25, t, 3H, 2.05, s, 3H, 4.25, qd, 2H, 5.3, s, 2H, 6.8, dd, 1H, 7.15 s, 1H, 7.3, d, 2H, 7.4-7.6 m, 3H.

An Overhauser effect (NO e.) Between the benzyl protons _(R4 = _R5 = H) and the protons _g2 = ₆ = H g

B. 1- (3,4-Dichlorobenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3-carboxylic acid

This compound was prepared as described in Step D of Preparation 1.30, starting from 1.5 g of the compound obtained in the previous step in 50 ml of EtOH and 0.3 g of KOH in 10 ml of water. 1.31 g of the expected product are obtained.

30983 / H

Preparation 1.32

1- (3-Chloro-4-methylbenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3-carboxylic acid

To a solution of 2.17 g of the compound described in Step B of Preparation 1.30 in 100 ml of toluene is added at room temperature and portionwise 0.72 g of sodium hydride 60% in oil and then heated to 65 ° C for 1 hour. After cooling to ambient temperature, 2.2 g of 3-chloro-4-methylbenzyl iodide is added dropwise and then heated to reflux for 20 hours. After cooling to ambient temperature, saturated aqueous NH ₄ Cl solution is added, decanted, the organic phase is washed with saturated NaCl solution, dried over MgSO ₄ and the solvent is evaporated off under vacuum. The residue is extracted with AcOEt, the organic phase is washed with saturated NaHCO ₃ solution, pH = 2 buffer solution, water, dried over MgSO ₄ , and the solvent is evaporated off under vacuum. The residue was taken up in cyclohexane / AcOEt (75/25, v / v), the precipitate was drained and 1.38 g of crude product was obtained. 0.35 g of this product is dissolved in AcOEt, cyclohexane is added until precipitation and the substance is drained. 0.17 g of the expected purified product is obtained, m.p. = 162 ° C.

NMR: .delta. (Ppm): 1.95-2.6, m, 6H, 5.2, s, 2H, 6.6-7.7, m, 7H, 12.845, sc, 1H.

An Overhauser effect (NOE) between the benzyl protons _(R4 = _R5 = H) and the protons _g2 = g6 = H

Preparation 1.33

1- (4-Methylbenzyl) -5- (4-chloro-3-methylphenyl) -4-methylpyrazole-3-carboxylic acid

A. 4'-Chloro-3'-methylpropiophenone

To a mixture of 18 ml of o-chlorotoluene and 22.7 g of aluminum chloride was added dropwise 16 g of propionyl chloride, and then the mixture was heated at 130 ° C for 3 hours. After cooling to ambient temperature, the reaction mixture is poured into a mixture of 100 ml of concentrated HCl and ice, extracted with ether, the organic phase is washed with saturated NaHCO ₃ solution, dried over Na ₂ SO ₄ and the solvent is evaporated off under vacuum. The residue is distilled under reduced pressure. 20.7 g of the expected product are obtained, which crystallizes, boiling point = 95 ° C at 5 Pa.

B. Ethyl lithium salt of 4- (4-chloro-3-methylphenyl) -3-methyl-4-oxydo-2-oxobut 3-enate

3C983 / H

This compound was prepared as described in Step A of Preparation 1.30 starting from a 50 ml solution of 1M lithium hexamethyldisilazane in tetrahydrofuran, 40 ml cyclohexane, 10 g of the compound obtained in the previous step in 70 ml cyclohexane and 9.8 g diethyl oxalate. After stirring overnight at room temperature, the reaction mixture was concentrated in vacuo, the residue was taken up in ether and the solvent was evaporated in vacuo. The residue is taken up in heptane and the precipitate formed is drained. 15 g of the expected product are obtained.

C. 5- (4-Chloro-3-methylphenyl) -4-methylpyrazole-3-carboxylic acid ethyl ester

A solution of 15 g of the compound obtained in the previous step in 150 ml of AcOH was cooled to 5 ° C, 2.5 ml of hydrazine monohydrate was added dropwise, and then the mixture was heated to reflux for 5 hours and left overnight with stirring at ambient temperature. The reaction mixture was poured into a water / ice, extracted with AcOEt, the organic phase is washed three times with saturated NaCl, dried over Na ₂ SO 4 and the solvent removed in vacuo. The residue is taken up in iso ether, the precipitate formed is drained, washed in iso ether and dried. 7.88 g of the expected product is obtained.

D. 1- (4-Methylbenzyl) -5- (4-chloro-3-methylphenyl) -4-methylpyrazole-3-carboxylic acid ethyl ester

To a suspension of 5 g of the compound obtained in the preceding step in 70 ml of toluene is added at ambient temperature and in portions 0.98 g of sodium hydride 60% in oil and then heated at 65 ° C for 1 hour. After cooling to ambient temperature, 3.7 g of 4-methylbenzyl bromide is added dropwise and then heated to reflux for one night. After cooling to ambient temperature, an aqueous 50% NH ₄ Cl solution was added, decanted, and the organic phase was concentrated in vacuo. The residue is extracted with AcOEt, the organic phase is washed twice with saturated NaCl solution. dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (80/20, v / v). 2.1 g of the expected product are obtained.

E. 1- (4-Methylbenzyl) -5- (4-chloro-3-methylphenyl) -4-methylpyrazole-3-carboxylic acid

To a solution of 2 g of the compound obtained in the previous step in 20 ml of EtOH is added at ambient temperature a solution of 0.439 g of KOH in 20 ml of water and then heated to a temperature of

30983 / H reflux for 3 hours. After cooling to ambient temperature, the reaction mixture is poured onto a mixture of HCl 1N and ice, the precipitate formed is drained, washed with water and dried under vacuum. 1.8 g of the expected product are obtained.

NMR: .delta. (Ppm): 2 to 2.4, m, 9H, 5.2, s, 2H, 6.7 to 7.6, m, 7H, 12.65, sc, 1H.

Preparation 1.34

1- (3,4-Dichlorobenzyl) -5- (4-chloro-3-methylphenyl) -4-methylpyrazole-3-carboxylic acid

A. 1- (3,4-Dichlorobenzyl) -5- (4-chloro-3-methylphenyl) -4-methylpyrazole-3-carboxylic acid ethyl ester

This compound is prepared as described in Step D of Preparation 1.33, starting from 2.5 g of the compound obtained in Step C of Preparation 1.33 in 50 ml of toluene, 0.8 g of sodium hydride 60% in oil and 2.4 g of 3.4 -dichlórbenzylbromidu. After hydrolysis by addition of aqueous 50% NH ₄ Cl solution, the organic phase is decanted, the insoluble material is filtered and the filtrate is concentrated in vacuo. The residue is extracted with AcOEt, the organic phase is washed twice with saturated NaCl solution, dried over Na ₂ SO <and the solvent removed in vacuo. The residue is chromatographed on silica gel, eluting with a cyclohexane / AcOEt mixture (80/20, v / v). 3 g of the expected product are obtained.

B. 1- (3,4-Dichlorobenzyl) -5- (4-chloro-3-methylphenyl) -4'-methylpyrazole-3-carboxylic acid

This compound was prepared as described in step E of Preparation 1.33, starting from 3 g of the compound obtained in the previous step in 20 ml EtOH and 0.5 c g KOH in 20 ml water. 2.7 g of the expected product are obtained.

NMR: .delta. (Ppm): 2, s, 3H, 2.3, m, 3H, 5.2, s, 2H, 6.7-7.6, m, 6H, 12.65, sc, 1H.

Preparation 1.35

1- (4-Chloro-3-methylbenzyl) -5- (4-chlorophenyl) -4- (ethoxymethyl) pyrazole-3-carboxylic acid

A. 1- (tert-Butoxycarbonyl) -5- (4-chlorophenyl) -4-methylpyrazole-3-carboxylic acid ethyl ester

To a solution of 6 g of the compound obtained in Step B of Preparation 1.30 in 150 ml of dioxane is added 4.62 ml of triethylamine, 6.57 g of di-tert-butyl dicarbonate and 1.18 g of sodium hydride 60%.

30983 / H in oil and then allowed to stir at ambient temperature for 72 hours. The insoluble component is filtered and the filtrate is concentrated in vacuo. The residue is taken up in cyclohexane, the precipitate formed is drained, washed in cyclohexane and dried. 6.23 g of the expected product are obtained.

B. 1- (tert-Butoxycarbonyl) -5- (4-chlorophenyl) -4- (bromomethyl) pyrazole ethyl ester

3-carboxylic acid

To a solution of 6.2 g of the compound obtained in the previous step in 150 ml of CCl ₄ was added 3.18 g of N-bromosuccinimide and 0.02 g of dibenzoyl peroxide and then heated to reflux for 1 night. The insoluble component is filtered and the filtrate is concentrated in vacuo. The residue is taken up in cyclohexane, decanted and the solvent is evaporated off under vacuum. 8.72 g of the expected product are obtained in the form of an oil.

C. 5- (4-Chloro-phenyl) -4- (ethoxymethyl) -pyrazole-3-carboxylic acid ethyl ester

Sodium (0.23 g) was added to EtOH (100 mL) and added dropwise after dissolution

4.5 g of the compound obtained in the previous step are heated to reflux for one night. Concentrate in vacuo and chromatograph the residue on silica gel eluting with cyclohexane / AcOEt (60/40, v / v). 2.26 g of the expected product are obtained.

D. 1- (3-Chloro-4-methylbenzyl) -5- (4-chlorophenyl) -4- (ethoxymethyl) pyrazole-3-carboxylic acid ethyl ester

To a solution of 1.65 g of the compound obtained in the preceding step in 50 ml of toluene is added at ambient temperature and in portions 0.254 g of sodium hydride 60% in oil and then heated at 65 ° C for 1 hour. After cooling to ambient temperature, 1.7 g of 3-chloro-4-methylbenzyl iodide is added dropwise and then heated to reflux for 20 hours. After cooling to ambient temperature, the insoluble component was filtered and the filtrate was concentrated in vacuo. The residue is extracted with AcOEt, the organic phase is washed with saturated NH ₄ Cl solution, pH = 2 buffer solution, water, dried over MgSO ₄ and the solvent is evaporated off under vacuum. The residue is. Chromatograph on silica gel eluting with cyclohexane / AcOEt (75/25, v / v). 0.90 g of product is obtained which is chromatographed on

30983-4 silica gel eluting with cyclohexane / AcOEt (80/20, v / v). 0.24 g of the expected product is obtained.

E. 1- (4-Chloro-3-methylbenzyl) -5- (4-chlorophenyl) -4- (ethoxymethyl) pyrazole-3-carboxylic acid

To a solution of 0.23 g of the compound obtained in the previous step in 10 ml of EtOH is added at ambient temperature a solution of 0.088 g of KOH in 10 ml of water and then heated to reflux for 3 hours. Concentrate in vacuo to a volume of 10 mL, add 10 mL of water, acidify to pH = 2.5 by adding 1 N HCl, drain the resulting precipitate and dry. 0.21 g of the expected product is obtained.

Preparation 1.36

1- (5-Chloro-indan-1-yl) -5- (4-chloro-phenyl) -pyrazole-3-carboxylic acid

To a suspension of 2.5 g of the compound obtained in Preparation B of Preparation 1.7 in 20 ml of toluene was added portionwise 0.88 g of sodium hydride 60% in oil, and then the mixture was heated at 65 ° C for 1 hour. After cooling to ambient temperature, a solution of 2.3 g of 1-bromo-5-chloroindane (Preparation 3.8) in 10 ml of toluene is added dropwise and heated at reflux overnight. The reaction mixture is cooled to 5 ° C, 20 ml of aqueous 50% NH ₄ Cl solution are added dropwise, decanted and the organic phase is concentrated in vacuo. The residue is extracted with AcOEt, the organic phase is washed with saturated NaCl, dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. 1.04 g of the expected product is obtained, which product is used as is.

Preparation 1.37

1- (4-Methoxybenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

A. 1- (4-Methoxybenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid methyl ester

To a suspension of 2.5 g of the compound obtained in Preparation B of Preparation 1.10 in 25 ml of toluene is added at room temperature and in portions 0.53 g of sodium hydride 60% in oil and then heated at 65 ° C for 1 hour. After cooling to ambient temperature, a solution of 1.7 g of 4-methoxybenzyl chloride in 25 ml of toluene was added dropwise and then heated to reflux for 20 hours. After cooling to ambient temperature

30983 / H is added 20 ml of aqueous 50% NH ₄ Cl solution, denatured and the organic phase is evaporated in vacuo. The residue is extracted with AcOEt, the organic phase is washed with saturated NaCl solution, dried over _MgSO4 and the solvent removed in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (80/20, v / v). 1.03 g of the expected product is obtained, which product is used as is.

B. 1- (4-Methoxybenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid

To a solution of 1.03 g of the compound obtained in the previous step in 20 ml of methanol is added at ambient temperature a solution of 0.23 g of KOH in 20 ml of water, and then the mixture is refluxed for 3 hours. After cooling to ambient temperature, the reaction mixture is poured into 1 N HCl / ice, extracted with ether, the organic phase is dried over Na ₂ SO ₄ and the solvent is evaporated off under vacuum. 0.8 g of the expected product is obtained, which product is used as is.

Preparation 1.38

1- (2,4-Dichlorobenzyl) -3- (4-chlorophenyl) pyrazole-5-carboxylic acid

A. 1- (2,4-Dichlorobenzyl) -3- (4-chlorophenyl) pyrazole-5-carboxylic acid methyl ester

To a solution of 0.8 g of the compound obtained in Step B of Preparation 1.7 in 15 ml of dimethylformamide is added at room temperature and in portions 0.16 g of sodium hydride 60% in oil and left for 30 minutes with stirring at room temperature. The reaction mixture was cooled to 0 ° C and a solution of 0.49 ml of 2,4-dichlorobenzyl chloride in 5 ml of dimethylformamide was added dropwise and then left to stir at ambient temperature for 16 hours. The reaction mixture is poured into ice water, the aqueous phase is washed with dichloromethane, the white precipitate is drained, washed with water and dried. 0.86 g of the expected product is obtained, m.p. = 120 ° C

B. 1- (2,4-Dichlorobenzyl) -3- (4-chlorophenyl) pyrazole-5-carboxylic acid

To a solution of 0.85 g of the compound obtained in the previous step in 15 ml of methanol is added a solution of 0.3 g of KOH in 5 ml of water, and then the mixture is refluxed for 3 hours. The reaction mixture is poured into 100 ml of ice-water, the precipitate formed is drained, washed with water and dried under vacuum. 0.79 g of the expected product is obtained, m.p. = 218 ° C.

3C983 / H

Preparation 2.1

(1S) -2-Endo-amino-1,3,3-trimethyl-bicyclo [2.2.1] heptane hydrochloride

A. (1S) -1,3,3-Trimethylbicyclo [2.2.1] heptan-2-one oxime

To a solution of 38.1 g of (1S) - (+) - fenchone in 120 ml of methanol is added at ambient temperature a solution of 23 g of hydroxylamine hydrochloride and 41 g of sodium acetate in 200 ml of water, and then the mixture is refluxed for 48 hours. hours. After cooling to ambient temperature, the precipitate is drained, washed with water and dried under vacuum. 41 g of the expected product are obtained.

B. (1S) -2-Endo-amino-1,3,3-trimethyl-bicyclo [2.2.1] heptane hydrochloride

A mixture of 8 g of the compound obtained in the previous step and 0.8 g of platinum oxide in 700 ml of EtOH and 20 ml of chloroform is hydrogenated in a Parr apparatus at ambient temperature and 6 bar for 48 hours. Filter the catalyst on Celite ^R and concentrate the filtrate in vacuo. The residue is taken up in ether and the precipitate formed is drained. 2.61 g of the expected product are obtained.

alpha ²⁰ _D = 4.6 ° C (c = 1, EtOH).

Preparation 2.2 (1S) -2endo, exo-amino-1,3,3-trimethylbicyclo [2.2.1] heptane

A solution of 10 g of the compound obtained in Step A of Preparation 2.1 in 70 ml of AcOH is cooled to 10 ° C, 25 g of Raney nickel are added and the mixture is allowed to warm to ambient temperature. The mixture is then hydrogenated for 24 hours at ambient temperature and atmospheric pressure. Filter the catalyst on Celite ^R , add 100 ml of water and ice to the filtrate, adjust to pH = 7 by adding concentrated NaOH, extract in ether, dry the organic phase over MgSO ₄ and evaporate the solvent in vacuo. 7.37 g of the expected product are obtained in the form of an oil (endo, exo mixture).

Preparation 2.3 (1R) -2-endo, exo-amino-1,3,3-trimethylbicyclo [2.2.1] heptane and (1R) -2-imino-1,3,3-trimethylbicyclo [2.2.1] heptane

A. (1R) -1,3,3-Trimethylbicyclo [2.2.1] heptan-2-one oxime

30983Ή

This compound is prepared as described in Step A of Preparation 2.1, starting from (1R) - (-) - fenchone.

B. (1R) -2endo, exo-amino-1,3,3-trimethylbicyclo [2.2.1] heptane and (1R) -2-imino-1,3,3-trimethylbicyclo [2.2.1] heptane

A solution of 14 g of the compound obtained in the preceding step in 100 ml of AcOH is cooled to 10 ° C, 35 g of Raney nickel are added and the temperature of the mixture is allowed to rise to ambient temperature. The mixture is then hydrogenated for 24 hours at ambient temperature and atmospheric pressure. Filter the catalyst on Celite ^R and add 100 ml of ice / water to the filtrate, adjust to pH = 7 by addition of concentrated NaOH, extract in ether, dry the organic phase over MgSO4 and evaporate the solvent in vacuo. 10.77 g of a mixture of the expected products are obtained.

Preparation 2.4

2exo- (Propylamino) -bicyclo [2.2.1] heptane hydrochloride

A. 2exo- (propionylamino) -bicyclo [2.2.1] heptane

A solution of 2 g of 2-aminoaminoborane and 20.5 ml of triethylamine in 80 ml of dichloromethane is cooled in an ice bath, a solution of 11.2 ml of propionyl chloride in 80 ml of dichloromethane is added dropwise and left to stir at room temperature overnight. After filtration of the reaction mixture, the filtrate is washed with saturated aqueous NaHCO ₃ solution, water, the organic phase is dried over MgSO ₄ and the solvent is evaporated off under vacuum. 23 g of the expected product are obtained.

B. 2exo- (Propylamino) -bicyclo [2.2.1] heptane hydrochloride

To a suspension of 7.6 g of lithium aluminum hydride in 100 ml of tetrahydrofuran is added dropwise a solution of 23 g of the compound obtained in the previous stage in 100 ml of tetrahydrofuran and then heated to reflux for 2 hours and left overnight with stirring. at ambient temperature. The reaction mixture is hydrolyzed by adding 10 ml of water and then 5 ml of 15% NaOH solution and 14 ml of water. After stirring for 15 minutes, the mineral salts were filtered and the filtrate was concentrated in vacuo. The oil obtained is taken up in iso ether, hydrochloric ether solution is added until pH = 1 and the precipitate formed is drained. The precipitate is taken up in AcOEt, extracted with water, the aqueous phase is basified to pH = 12 by addition of NaOH 5N solution, extracted

3C 983 / H in AcOEt, the organic phase is washed with water, dried over MgSO ₄ and the solvent is evaporated off under vacuum. The product obtained is taken up in iso ether, hydrochloric ether solution is added until pH = 1 and the precipitate formed is drained. 14 g of the expected product are obtained, m.p. = 230 DEG C. (dec.).

Preparation 2.5

3endo-Amino-bicyclo [3.2.1] octane hydrochloride

This compound was prepared as described by H. Maskill et al., J. Chem. Soc. Perkin Trans. II, 1984, 1369-1376.

Preparation 2.6

(1R) -2-Endo-amino-1,3,3-trimethyl-bicyclo [2.2.1] heptane hydrochloride

A mixture of 15.5 g of the compound obtained in Step A of Preparation 2.3 and 2 g of platinum oxide in 500 ml of EtOH and 14 ml of chloroform is hydrogenated in a Parr apparatus at ambient temperature and at a pressure of 8 bar. Filter the catalyst on Celite ^R and concentrate the filtrate in vacuo. The residue was taken up in hydrochloric ether and the solvent was evaporated in vacuo. The residue was taken up in hexane, the insoluble material was filtered, and the solvent was concentrated in vacuo. 5.64 g of an oil are obtained, which crystallizes over time. The crystals formed are discarded, taken up in hexane, discarded again and washed. 0.85 g of the expected product is obtained.

alpha ²⁰ _D = + 1 ° (c = 1, EtOH)

Preparation 2.7

2,2,6,6-Tetramethylcyclohexylamine

A. 2,2,6,6-tetramethylcyclohexanone oxime

To a solution of 3.4 g of 2,2,6,6-tetramethylcyclohexanone in 2 ml of methanol is added at ambient temperature a solution of 2.3 g of hydroxylamine hydrochloride and 3.6 g of sodium acetate in 20 ml of water, and then the mixture is heated to reflux for 48 hours. After cooling to ambient temperature, the precipitate formed is drained, washed with water and dried under vacuum. 1.2 g of the expected product are obtained.

B. 2 ', 2', 6 ', 6'-tetramethylcyclohexylamine

30983 H

A solution of 1 g of the compound obtained in the preceding step in 30 ml of AcOH is cooled to 10 ° C under a nitrogen atmosphere, 2.5 g of Raney nickel are added and the temperature is allowed to rise to ambient temperature. The mixture thus obtained is hydrogenated at ambient temperature and atmospheric pressure for 24 hours. Filter the catalyst on Celite ^R , add water / ice to the filtrate, adjust to pH = 7 by adding concentrated NaOH, extract with AcOEt, dry the organic phase over Na ₂ SO ₄ and evaporate the solvent in vacuo. 0.63 g of the expected product is obtained.

Preparation 3.1

3-Fluoro-4-methylbenzyl bromide

A. 3-Fluoro-4-methylbenzoic acid ethyl ester

150 ml of EtOH are cooled in an ice bath, 10 ml of thionyl chloride are slowly added, and then 10 g of 3-fluoro-4-methylbenzoic acid are added and the temperature is allowed to rise to ambient temperature with stirring. The reaction mixture was heated to reflux for 2 hours and then concentrated in vacuo. In this way it is obtained

10.45 g of the expected product in the form of an oil.

B. 3-Fluoro-4-methylbenzyl alcohol

A suspension of 3.26 g of aluminum and lithium hydride in 100 L of tetrahydrofuran is cooled to 0 ° C, a solution of 10.45 g of the compound described above in 50 ml of tetrahydrofuran is added dropwise and left under stirring until the temperature rises. ambient temperature. Then, the reaction mixture is heated to reflux for 3 hours, 1.5 g of lithium aluminum hydride are added and heating is continued at reflux for 48 hours. After cooling to ambient temperature, the reaction mixture is hydrolyzed by adding a saturated aqueous solution of NH ₄ Cl and then decanting and preserving the organic phase. The aqueous phase was extracted with tetrahydrofuran and the combined organic phases were dried over _MgSO4 and the solvent removed in vacuo. 7.87 g of the expected product are obtained in the form of an oil.

C. 3-Fluoro-4-methylbenzyl bromide

A mixture of 7.8 g of the compound obtained in the preceding step in 112 ml of a 47% HBr solution in water is heated at 100 ° C for 2 hours. After cooling to temperature

30983 / H RT, the reaction mixture was extracted with ether, the organic phase is dried over _MgSO4 and the solvent removed in vacuo. 11.15 g of the expected product are obtained in the form of an oil which is used as is.

Preparation 3.2

3-chloro-4-methylbenzyl

To a solution of 9.6 g of 3-chloro-4-methylbenzyl chloride in 15 ml of acetone is added dropwise a solution of 8.5 g of sodium iodide in 25 ml of acetone and left to stir at ambient temperature for 48 hours. The formed sodium chloride is filtered, the filtrate dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. 13 g of the expected product are obtained in the form of an oil which is used as is.

Preparation 3.3

3-chloro-4-fluorobenzyl bromide

To a mixture of 5 g of 3-chloro-4-fluorotoluene in 100 ml of CCl ₄ is added 0.05 g of dibenzoyl peroxide followed by 6.1 g of N-bromosuccinimide and heated to reflux for 12 hours. The insoluble portion is filtered and washed with CCl ₄ . The filtrate was washed with water, saturated NaCl solution, the organic phase over Na ₂ SO ₄ and the solvent evaporated in vacuo. 7.5 g of the expected product are obtained in the form of an oil which is used as is.

Preparation 3.4

1- (1-Bromomethyl) -2,4-dichlorobenzene mL of a 33% solution of HBr in AcOH was cooled to 0 ° C, 2 mL of 2,4-dichloro-1- (1-hydroxyethyl) benzene was added dropwise and allowed to stand. for 30 minutes with stirring at 0 ° C and then for 3 hours at ambient temperature. The reaction mixture is poured into ice water, extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO ₃ solution, water, saturated NaCl solution, dried over MgSO ₄ and the solvent is evaporated off under vacuum. 3.4 g of the expected product are obtained.

30983 / H

Preparation 3.5

4-Ethylbenzene bromide ml of a 33% solution of HBr in AcOH is cooled to 0 ° C, 5 g of 4-ethylbenzyl alcohol is added dropwise and left stirring at 0 ° C for 30 minutes and then at ambient temperature for 3 hours. The reaction mixture was poured into 200 ml of ice water, extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO3, saturated NaCl, dried over _MgSO4 and the solvent removed in vacuo. 5.6 g of the expected product are obtained.

Preparation 3.6

- (1-Bromomethyl) -3,4-dichlorobenzene

This compound was prepared as described in Preparation 3.4 starting from 25 ml of a 33% solution of HBr in AcOH and 5 g of 3,4-dichloro-1- (1-hydroxyethyl) benzene. 6.4 g of the expected product are obtained.

Preparation 3.7

- (1-Bromomethyl) -4-methylbenzene

This compound was prepared as described in Preparation 3.4 starting from 30 ml of a 33% solution of HBr in AcOH and 7 ml of 1- (1-hydroxyethyl) -4-methylbenzene. 9 g of the expected product are obtained.

Preparation 3.8

bromo-5-chloroindan

A. 1-Hydroxy-5-chloroindane

A mixture of 5-chloroindan-1-one (2.5 g) in tetrahydrofuran (30 ml) was cooled to 0-5 ° C, concentrated NaOH (2.5 ml) was added, followed by 0.88 g of sodium borohydride in portions and left overnight with stirring at ambient temperature. The reaction mixture is poured into 100 ml of water, acidified to pH = 2 by addition of concentrated HCl solution, extracted with AcOEt, the organic phase is washed with saturated NaCl solution, dried over Na ₂ SO ₄ and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (80/20, v / v). 2.1 g of the expected product are obtained.

30983

B. 1-Bromo-5-chloroindane ml of a 33% solution of HBr in AcOH is cooled to 0 ° C, 2 g of the compound obtained in the previous stage are added dropwise, left under stirring at 0 ° C for 30 minutes and then for 3 hours at ambient temperature. The reaction mixture is poured into 200 ml of ice-water, extracted with AcOEt, the organic phase is washed with saturated NaHCO ₃ solution, saturated NaCl solution, dried over Na ₂ SO ₄ and the solvent is evaporated off under vacuum. 2.8 g of the expected product are obtained.

Example 1

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (3,4-dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxamide

A. 1- (3,4-Dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid chloride

To a solution of 5.1 g of the compound obtained in Preparation 1.1 in 50 ml of toluene, 1.52 ml of thionyl chloride is added at ambient temperature and then heated to reflux for 4 hours and left to stir at room temperature overnight. The reaction mixture was concentrated in vacuo, the residue was taken up in ether and the solvent was evaporated in vacuo. 5.17 g of the expected product are obtained in the form of an oil.

B. N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3,4-dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxamide

To a solution of 0.38 g of the compound obtained in Preparation 2.1 and 0.554 ml of triethylamine in 50 ml of dichloromethane is added at ambient temperature 0.759 g of the compound obtained in the previous stage and left to stir at room temperature overnight. The reaction mixture is concentrated in vacuo, the residue is extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO ₃ solution, pH = 2 buffer solution, water, dried over MgSO ₄ and the solvent is evaporated off under vacuum. The residue is taken up in hexane, the precipitate formed is drained and dried. 0.67 g of the expected product is obtained, m.p. = 137 ° C.

30983 / H alpha ²⁰ _D = + 1 ° (c = 1, EtOH)

Example 2

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2exo-yl] -1- (3,4-dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxamide

To a solution of 0.5 g of the compound obtained in Preparation 2.2 and 0.364 ml of triethylamine in 50 ml of dichloromethane is added at ambient temperature 1 g of the compound obtained in Stage A of Example 1 and left to stir at room temperature overnight. It is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO3 solution, with a buffer solution of pH 2 and with water, dried over _MgSO4 and the solvent removed in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (75/25, v / v). Two isomers are separated:

- less polar isomer, compound of Example 1,

- more polar isomer, expected compound.

0.08 g, m.p. = 101 ° C.

NMR: .delta. (Ppm): 0.6-2, m, 16H, 2.3, s, 3H, 3.45, d, 1H, 5.4, s, 2H, 6.8, s, 1H,

6.9, dd, 1H, 7.1-7.4, m, 6H, 7.5, d, 1H, 10.

Example 3 and Example 4

N - [(1R) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3,4-dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxamide (Example 3) and

N - [(1R) -1,3,3-trimethylbicyclo [2.2.1] hept-2exo-yl] -1- (3,4-dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxamide (Example 4)

To a solution of 0.5 g of a mixture of the compounds obtained in Preparation 2.3 and 0.364 g of triethylamine in 50 ml of dichloromethane is added at ambient temperature 1 g of the compound obtained in Stage A of Example 1 and left to stir at room temperature overnight. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO ₃ solution, pH = 2 buffer solution, water, dried over MgSO ₄ and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (75/25 by volume). Different compounds are separated:

30983 ^from H

- less polar isomer, compound of Example 3: 0.07 g, m.p. = 130 ° C

NMR: .delta. (Ppm): 0.6-1.9, m, 16H, 2.3, s, 3H, 3.65, d, 1H, 5.4, s, 2H, 6.85, s, 1H .

6.9, dd, 1H, 7.0, d, 1H, 7.15 to 7.4, m, 5H, 7.5, d, 1H

Example 4: 0.09 g, mp = 121 ° C

NMR: .delta. (Ppm): 0.6-2, m, 16H, 2.3, s, 3H, 3.4, d, 1H, 5.4, s, 2H, 6.8, s, 1H, 6 9, dd, 1H, 7.1-7.4, m, 5H, 7.5, d, 1H

- and the most polar compound

N - [(1 R) -1,3,3-trimethylbicyclo [2.2.1] hept-2-ylidene] -1- (3,4-dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxamide; 0.54 g is obtained.

Example 5

N- [bicyclo [2.2.1] hept-2exo-yl] -N-propyl-1- (3,4-dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxamide

To a solution of 0.266 g of the compound obtained in Preparation 2.4 and 0.48 ml of triethylamine in 50 ml of dichloromethane is added at room temperature 0.66 g of the compound obtained in Stage A of Example 1 and left to stir at room temperature overnight. The reaction mixture is concentrated under vacuum, the residue is extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO 3, pH = 2, water, dried over MgSO ₄ and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (70/30, v / v). 0.5 g of the expected product is obtained, m.p. = 108 ° C.

Example 6

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (3-fluoro-4-methylbenzyl) -5- (4-methylphenyl) pyrazole-3-carboxamide

A. 1- (3-Fluoro-4-methylbenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylic acid chloride and 1- (3-fluoro-4-methylbenzyl) -3- (4-methylphenyl) chloride pyrazole-5-carboxylic acid

To a solution of 0.9 g of a mixture of the compounds obtained in Preparation 1.3 in 50 ml of toluene is added 0.3 ml of thionyl chloride at ambient temperature and then heated to reflux for 5 hours and left to stir at room temperature overnight. Reaction mixture

The 30983 / H was concentrated in vacuo, the residue was taken up in ether and the solvent was evaporated in vacuo. 1 g of a mixture of the expected products is obtained.

B. N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3-fluoro-4-methylbenzyl) -5- (4-methylphenyl) pyrazol-3 amide

To a solution of 0.33 g of the compound obtained in Preparation 2.1 and 0.48 ml of triethylamine in 50 ml of dichloromethane is added at ambient temperature 0.63 g of a mixture of the compounds obtained in the previous stage and left under stirring at ambient temperature for 48 hours. . The reaction mixture is concentrated in vacuo, the residue is extracted with AcOEt, the organic phase is washed with saturated aqueous NaHCO 3, pH = 2, water, dried over MgSO ₄ and the solvent is evaporated off under vacuum. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (75/25 by volume). Two compounds are separated:

- less polar isomer, compound of Example 6: 0.5 g is obtained, melting point = 53 ° C alpha ² ° o = -3.3 ° (c = 1, EtOH)

- more polar isomer:

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (3-fluoro-4-methylbenzyl) -3- (4-methylphenyl) pyrazole-5-carboxamide

Example 7

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (3-chloro-4-methylbenzyl) -5- (4-methoxyphenyl) pyrazole-3-carboxamide

A. 1- (3-Chloro-4-methylbenzyl) -5- (4-methoxyphenyl) pyrazole-3-carboxylic acid chloride 1- (3-chloro-4-methylbenzyl) -3- (4-methoxyphenyl) pyrazole -5-carboxylic acid A mixture of the two compounds was prepared as described in Step A of Example 6, starting from 1.7 g of the mixture of compounds obtained in Preparation 1.5, 0.54 ml of thionyl chloride and 50 ml of toluene. 1.77 g of a mixture of the expected products are obtained.

B. N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3-chloro-4-methylbenzyl) -5- (4-methoxyphenyl) pyrazole-3-carboxamide

30983, Ή

This compound was prepared as described in Example 6, Step B starting from 0.531 g of the compound obtained in Preparation 2.1, 0.775 ml of triethylamine, 100 ml of dichloromethane and 1 g of a mixture of the compounds obtained in the previous step. Chromatograph on silica gel eluting with cyclohexane / AcOEt (75/25, v / v). Two compounds are separated:

- less polar isomer, compound of Example 7: 0.77 g is obtained, melting point = 116 ° C and ²⁰ _D = -1.1 ° (c = 1, EtOH)

- more polar isomer:

N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3-chloro-4-methylbenzyl) -3- (4-methoxyphenyl) pyrazole-5-carboxamide

Example 8

N- (adamant-2-yl) -1- (2,4-dichlorobenzyl) -5- (4-chlorophenyl) pyrazole-3-carboxamide

A. 1- (2,4-Dichlorobenzyl) -5- (4-chlorophenyl) pyrazole-3-carboxylic acid chloride

This compound was prepared as described in Example A, Step A, starting from 3.27 g of the compound obtained in Preparation 1.7, 2.2 ml of thionyl chloride and 60 ml of toluene. 3.25 g of the expected product are obtained, which product is used as is.

B. N- (adamant-2-yl) -1- (2,4-dichlorobenzyl) -5- (4-chlorophenyl) pyrazole-3-carboxamide

A solution of 0.39 g of 2-aminoadamantane hydrochloride and 0.58 ml of triethylamine in 15 ml of dichloromethane is cooled to 0 [deg.] C., a solution of 0.8 g of the compound obtained in the previous step in 15 ml of dichloromethane is added dropwise. hours with stirring at ambient temperature. Pour the reaction mixture to 50 ml. of ice water, after decantation, the organic phase is washed with water, saturated NaCl, dried over _MgSO4 and the solvent removed in vacuo. 0.42 g of the expected product is obtained after crystallization and then recrystallization in dichloromethane / iso ether, m.p. = 154 ° C.

3C9S3 / H

Example 9

N- [endo-bicyclo [3.2.1] oct-3-yl] -1- (2,4-dichlorobenzyl) -5- (4-chlorophenyl) pyrazole-3-carboxamide

This compound was prepared as described in Example 8, Step B starting from 0.17 g of the compound obtained in Preparation 2.5, 0.3 ml of triethylamine in 10 ml of dichloromethane and 0.41 g of the compound obtained in Stage A of Example 8 in 10 ml. dichloromethane. The product obtained is purified by chromatography on silica gel, eluting with a gradient of toluene / AcOEt (97/3, v / v) to (95/5, v / v). 0.43 g of the expected product is obtained, m.p. = 130 ° C.

Example 10

N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1 - [(1R, S) -1- (2,4-dichlorophenyl) ethyl] -

5- (4-chlorophenyl) pyrazole-3-carboxamide

A. 1- [1- (2,4-Dichlorophenylethyl) -5- (4-chlorophenyl) pyrazole-3-carboxylic acid chloride

This compound was prepared according to the procedure described in Step A of Example 1, starting from 0.68 g of the compound obtained in Preparation 1.14, 0.45 ml of thionyl chloride and 30 ml of toluene. 0.86 g of the expected product is obtained.

B. N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1 - [(1R, S) -1- (2,4-dichlorophenyl) ethyl] 5- (4-chlorophenyl) pyrazole-3-carboxamide

This compound was prepared as described in step B of Example 8, starting from 0.34 g of the compound obtained in Preparation 2.1 and 0.5 ml of triethylamine in 15 ml of dichloromethane and 0.72 g of the compound obtained in the previous step in 15 ml of dichloromethane. The product obtained is purified by chromatography on silica gel, eluting with a toluene / AcOEt mixture (96/4, v / v). 0.84 g of the expected product is obtained, m.p. = 70 ° C.

Example 11

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (3,4-dichlorobenzyl) -5- (2,6-dimethoxyphenyl) pyrazole-3-carboxamide

A. 1- (3,4-Dichlorobenzyl) -5- (2,6-dimethoxyphenyl) pyrazole-3-carboxylic acid chloride

3C983 / H

This compound was prepared as described in Example A, Step A, starting from 1.1 g of the compound obtained in Preparation 1.15, 0.6 ml of thionyl chloride and 25 ml of toluene. 1 g of the expected product is obtained.

B. N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3,4-dichlorobenzyl) -5- (2,6-dimethoxyphenyl) pyrazole-3-carboxamide

This compound was prepared as described in Example B, Step B starting from 0.303 g of the compound obtained in Preparation 2.1 and 0.4 ml of triethylamine in 15 ml of dichloromethane, 0.6 g of the compound obtained in the previous step in 15 ml of dichloromethane. Purification is performed by crystallization in cyclohexane / AcOEt (75/25, v / v). 0.53 g of the expected product is obtained.

α ²⁰ ° = + 1.2 ° (c = 1, EtOH)

Following the methods described in the previous examples, starting from the appropriate acid chlorides obtained from the acids described in the Preparations and the compound obtained in Preparation 2.1, the compounds of the invention described in Table 2 below are prepared.

Table 2

Pr. 93 94 W2 w ₃ W4 mp ° C '20 CC D {C = l, EtOH ) 12 (a) H Me H Cl M e 116 -3.3 ° 13 (a) H OMe H Cl Cl 55 - 14 (a) H F H Cl Me 114 -1.7 ° 15 (b) H Cl Cl H Cl - + 0.4 ° 16 (0 Me Me H Cl Me 65 -1.5 ° 17 (a) Me Me H Cl F 138 -1.5 ° 18 (a) Me Cl H H Me 59 -3.1 ° 19 (a) Me Cl H H F 158 -2.4 ° 20 (a) Me Cl H Cl Me 74 -2.4 ° 21 (a) Me Cl H Cl F 125 -2.5 ° 22 d Me Me H H F 175 -3.3 ° (C = l, DMF) 23 e H Me Cl H Cl 14 0 + 0.5 ° 24 (f) Me . Cl H H et 80 -2.1 ° 25 (g) Me Cl H Cl Cl 112 + 0.4 ° 26 (f) Me Cl Cl H Cl 64 -1 ° 27 (f) Cl Cl H H Me 110 -1.1 ° 28 (f) Cl Cl H Cl Me 49 -1.2 ° 29 (f) H SMe Cl H Cl 128.2 + 1.4 ° 30 (f) H cf ₃ Cl H Cl 113, 8 + 1.3 ° 31 (f) Me Cl H H OMe 115 + 2.3 °

a) This compound was prepared as described in Example 1, step A, then step B. The product was purified by chromatography on silica gel eluting with cyclohexane / AcOEt (75/25, v / v).

b) This compound was prepared as described in Example 8, step A and then step B. The product obtained was purified by chromatography on silica gel eluting with toluene / AcOEt (90/10, v / v).

c) This compound was prepared as described in Example 1, step A and then step B. The product was purified by chromatography on silica gel eluting with cyclohexane / AcOEt (80/20, v / v).

d) This compound was prepared as described in Example 1, step A and then step B. The product was purified by crystallization in AcOEt.

e) This compound was prepared as described in Example 1, Step A and then Step B. The product was purified by crystallization in iso ether.

f) This compound was prepared as described in Example 32, step A and then step B using the compound obtained in Preparation 2.1. The product is purified by chromatography on silica gel eluting with cyclohexane / AcOEt (80/20, v / v).

g) This compound was prepared as described in Example 32, Step A and then Step B using the compound obtained in Preparation 2.1. After drying over Na ₂ SO ₄ , the solvent is partially concentrated, the precipitate formed is drained, washed in iso ether and dried.

Example 32

N - [(1 R) -1,3,3-trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (4-methylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxamide

A. 1- (4-Methylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid chloride

This compound was prepared as described in Example A, Step A, starting from 2.8 g of the compound obtained in Preparation 1.10, 1.7 ml of thionyl chloride and 50 ml of toluene. 2.9 g of the expected product are obtained.

B. N - [(1R) -1,3,3-Trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (4-methylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxamide

30983 / H

To a solution of 0.765 g of the compound obtained in Preparation 2.6 and 1 ml of triethylamine in 20 ml of dichloromethane is added dropwise a solution of 1.6 g of the compound obtained in the previous stage in 20 ml of dichloromethane and left to stir at room temperature overnight. surroundings. Concentrate in vacuo, remove the residue in AcOEt, filter the insoluble matter, wash the filtrate with saturated aqueous NaHCO ₃ , pH = 2, saturated aqueous NaCl, dry over Na ₂ SO ₄ and evaporate the solvent in vacuo. The residue is chromatographed on silica gel, eluting with a cyclohexane / AcOEt mixture (75/25, v / v), m.p. = 108 ° C.

α ² ° ο = + 0.3 ° (c = 1, EtOH).

Example 33

N - [(1 R) -1,3,3-trimethylbicyclo [2.2.1] hept-2-exo-yl] -1- (4-methylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxamide

To a solution of 0.4 g of a mixture of the compounds obtained in Preparation 2.3 in 10 ml of dichloromethane is added 0.6 ml of triethylamine followed by a dropwise solution of 0.66 g of the compound obtained in Stage A of Example 32 in 10 ml of dichloromethane and left overnight with stirring at ambient temperature. Concentrate in vacuo, extract the residue in AcOEt, filter the insoluble matter, wash the filtrate twice with saturated aqueous NaHCO ₃ solution, twice with pH = 2 buffer solution, twice with saturated aqueous NaCl solution, dry over Na ₂ SO ₄ and evaporate the solvent in vacuo . The residue is chromatographed on silica, eluting with a cyclohexane / AcOEt mixture (80/20, v / v). A mixture containing 58% of the compound of Example 33 (exo form) and 41.6% of the compound of Example 32 (endo form) (determination by analytical HPLC) is thus obtained. Two isomers are separated by preparative HPLC:

Sample to be purified 0.31 g dissolved in 13 ml of starting diluent (A / B: 10% / 90%) supplemented with 9 ml of methanol and 4 ml of acetonitrile. In this way, after freeze-drying:

Example 33: m = 0.084 g, purity 100% (analytical HPLC) with TR = 41 mn.

? ² % = 8.8 ° (c = 1, EtOH).

30983 H

NMR: .delta. (Ppm): 0.8-1.15, 3s, 9H, 1.2-2, m, 7H, 2.2-2.25, m, 6H, 3.5, d, 1H, [delta] 4, s, 2H, 8 to 7.7, m, 9H,

Example 32: m = 0.056 g, purity 98% (analytical HPLC) with TR = 43.9 nm.

Example 34

Ibicyclo [2.2.1] hept-2exo-yl] -1- (4-methylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3- (1S) -1,3,3-trimethyl carboxamide

To a solution of 0.853 g of the compound obtained in Preparation 2.2 in 20 ml of dichloromethane is added

1.5 ml of triethylamine and then dropwise a solution of 1.6 g of the compound obtained in stage A of Example 32 in 20 ml of dichloromethane and left overnight at room temperature with stirring. Concentrate in vacuo, extract the residue in AcOEt, filter the insoluble matter, wash the filtrate twice with saturated aqueous NaHCO ₃ solution, twice with pH = 2 buffer solution, twice with saturated aqueous NaCl solution, dry over Na ₂ SO ₄ and evaporate the solvent. under vacuum. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (80/20, v / v). A mixture containing 58% of the compound of Example 34 (exo form) and 37% of the compound of Example 18 (endo form) (determination by analytical HPLC) is thus obtained. Two isomers are separated by preparative HPLC:

- sample for purification 0,23 g dissolved in 13 ml of starting diluent (A / B: 10% / 90%) supplemented with 3 ml of methanol and 9 ml of acetonitrile. In this way, after freeze-drying:

Example 34: m = 0.16 g, purity 99.6% (analytical HPLC) with TR = 34.7 min, mp = 49 ° C.

α ² % = -6.8 ° (c = 1, EtOH)

NMR: .delta. (Ppm): 0.8-1.15, 3s, 9H, 1.2-2, m, 7H, 2.1-2.4, m, 6H, 3.5, d, 1H,

5.4, s, 2H, 6.8-7.0, m, 9H.

Example 18: m = 0.066 g, purity 94.7% (analytical HPLC) with TR = 37.2 mn.

30983.Ή

Example 35

N- (2,2,6,6-tetramethylcyclohex-1-yl) -1- (4-methylbenzyl) -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxamide

To a solution of 0.25 g of the compound obtained in Preparation 2.7 in 15 ml of dichloromethane is added 0.4 ml of triethylamine and then a solution of 0.55 g of the compound obtained in Stage A of Example 32 in 15 ml of dichloromethane is added dropwise. stirring at ambient temperature. Concentrate in vacuo, extract the residue in AcOEt, wash the filtrate twice with saturated aqueous NaHCO ₃ solution, twice with pH = 2 buffer solution, twice with saturated aqueous NaCl solution, dry over Na ₂ SO _4, and evaporate the solvent in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (80/20, v / v). 0.1 g of the expected product is obtained.

Example 36

N- [bicyclo [2.2.1] hept-2exo-yl] -1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxamide

A. 1- (3-Chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxylic acid chloride

This compound was prepared as described in Example A, Step A, starting from 10 g of the compound obtained in Preparation 1.22, 5.5 ml of thionyl chloride and 125 ml of toluene. 9.41 g of the expected product are obtained.

B. N- [bicyclo [2.2.1] hept-2exo-yl] -1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxamide

A solution of 1.5 g of the compound obtained in the previous step in 15 ml of dichloromethane is added at ambient temperature to a solution of 0.411 g of 2-hexaminonorbornane and 1 ml of triethylamine in 15 ml of dichloromethane and left to stir at room temperature overnight. The reaction mixture is concentrated in vacuo, the residue is extracted with AcOEt, the insoluble material is filtered, the organic phase is washed with saturated aqueous NaHCO ₃ solution, pH = 2 buffer solution, water, dried over MgSO ₄ and the solvent evaporated in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (80/20, v / v). 0.5 g of the expected product is obtained, m.p. = 145.6 ° C.

30983 / H

Example 37

N- [bicyclo [2.2.1] hept-2exo-yl] -N-propyl-1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxamide

This compound was prepared as described in Example 36, Step B starting from 0.695 g of the compound obtained in Preparation 2.4, 1 ml of triethylamine in 15 ml of dichloromethane and 1.5 g of the compound obtained in Stage A of Example 36 in 15 ml of dichloromethane. 0.417 g of the expected product is obtained.

Example 38

N- (2-methyl-cyclohex-1-yl) -1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxamide

This compound was prepared as described in step B of Example 36 starting from 1 ml of 2-methylcyclohexylamine, 1 ml of triethylamine in 15 ml of dichloromethane and 1.5 g of the compound obtained in step A of Example 36 in 15 ml of dichloromethane. The compound is purified by chromatography on silica gel eluting with dichloromethane / methanol (98/2, v / v). 0.27 g of the expected product is obtained, m.p. = 165 ° C.

Example 39

N- (2,6-dimethyl-cyclohex-1-yl) -1- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxamide

This compound was prepared as described in Example 36, Step B starting from 0.605 g of 2,6-dimethylcyclohexylamine hydrochloride, 1 ml of triethylamine in 15 ml of dichloromethane and 1.5 g of the compound obtained in Step A of Example 36 in 15 ml of dichloromethane. 0.6 g of the expected compound is obtained, m.p. = 59.9 ° C.

Example 40

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1 - [(1 R, S) -1- (3,4-dichlorophenyl) ethyl] -5- (4 methylphenyl) pyrazole-3-carboxamide

A. 1- [1- (3,4-Dichlorophenyl) ethyl] -5- (4-methylphenyl) pyrazole-3-carboxylic acid chloride

To a suspension of 1.2 g of the compound obtained in Preparation 1.25 in 50 ml of toluene, 0.7 ml of thionyl chloride is added at ambient temperature and then heated to reflux.

30983 / H for 2 hours. After cooling to ambient temperature, the reaction mixture was concentrated in vacuo, the residue was taken up in toluene and the solvent was evaporated in vacuo. 1.3 g of the expected product are obtained.

B. N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2-eno-yl] -1 - [(1R, S) -1- (3,4-d) lor- Phenyl) ethyl] -5- (4-methylphenyl) pyrazole-3-carboxamide

To a solution of 0.341 g of the compound obtained in Preparation 2.1 in 15 ml of dichloromethane is added 0.6 ml of triethylamine and then dropwise a solution of 0.7 g of the compound obtained in the previous step in 15 ml of dichloromethane and left under stirring at room temperature overnight. . The mixture is concentrated in vacuo, the residue is extracted with AcOEt, the insoluble material is filtered, the filtrate is washed with saturated aqueous NaHCO ₃ solution, pH = 2 buffer solution, saturated aqueous NaCl solution, dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (80/20, v / v). 0.54 g of the expected product is obtained, m.p. = 112 ° C.

NMR: .delta. (Ppm): 0.6-1.9, m, 19H, 2.3, s, 3H, 3.6, mt, 1H, 5.55, qd, 1H, 6.6-6

7.6, m, 9H.

Example 41

N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1 - [(1R, S) -1- (4-methylphenyl) propyl] -5- (4-chloro) 3-methylphenyl) pyrazole-3-carboxamide

A. 1- [1- (4-Methylphenyl) propyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid chloride

This compound was prepared as described in Example 40, Step A, starting from 0.87 g of the compound obtained in Preparation 1.28 in 50 ml of toluene and 0.26 ml of thionyl chloride. 0.89 g of the expected product is obtained.

B. N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1 - [(1R, S) -1- (4-methylphenyl) -propyl] 5- ( 4-chloro-3-methylphenyl) pyrazole-3-carboxamide

To a solution of 0.51 g of the compound obtained in the previous step and 0.25 g of the compound obtained in Preparation 2.1 in 50 m of dichloromethane is added 0.363 ml of triethylamine and left under stirring at room temperature for 72 hours. Concentrate in vacuo, extract the residue in AcOEt, filter the insoluble matter, wash the filtrate with saturated

30983 / H aqueous NaHCO ₃ solution, pH = 2 buffer solution, saturated NaCl solution, dried over Na ₂ SO _4, and the solvent evaporated in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (75/25, v / v). 0.44 g of the expected product is obtained, m.p. = 136 ° C.

NMR: .delta. (Ppm): 0.5-2.6, m, 27H, 3.75, d, 1H, 4.95, dd, 1H, 6.6-7.4, m, 9H.

Example 44

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- [1-methyl-1- (4-methylphenyl) ethyl] -5- (4-chloro-3 methylphenyl) pyrazole-3-carboxamide

A. 1- [1-Methyl-1- (4-methylphenyl) ethyl] -5- (4-chloro-3-methylphenyl) pyrazole-3-carboxylic acid chloride

This compound was prepared as described in Example 40, Step A, starting from 1.5 g of the compound obtained in Preparation 1.29 in 100 ml of toluene and 0.44 ml of thionyl chloride. 1.55 g of the expected product are obtained.

B. N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- [1-methyl-1- (4-methylphenyl) ethyl] 5- (4-chloro) 3-methylphenyl) pyrazole-3-carboxamide

To a solution of 0.59 g of the compound obtained in the previous step and 0.29 g of the compound obtained in Preparation 2.1 in 50 ml of dichloromethane is added 0.424 ml of triethylamine and left to stir at room temperature overnight. Concentrate in vacuo, extract the residue in AcOEt, filter the insoluble matter, wash the filtrate with saturated aqueous NaHCO ₃ solution, pH = 2 buffer solution, saturated NaCl solution, dry over Na ₂ SO _4, and evaporate the solvent in vacuo. The residue is chromatographed on silica gel eluting with dichloromethane / methanol (97.5 / 2.5, v / v). 0.3 g of the expected product is obtained, m.p. = 195 ° C.

and ² ° D = -6.5 ° (c = 0.64, dichloromethane).

Example 45

N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (2,4-dichlorobenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3 amide

A. 1- (2,4-Dichlorobenzyl) -5- (4-chlorophenyl) -4-methylpyrazolecarboxylic acid chloride

3C983 / H

To a solution of 0.71 g of the compound obtained in Preparation 1.30 in 50 ml of toluene was added at room temperature 0.191 ml of thionyl chloride and then heated to reflux for one night. It is concentrated under vacuum, the residue is taken up in toluene and the solvent is evaporated off under vacuum. 0.72 g of the expected product is obtained in the form of an oil which is converted to a solid.

BN - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (2,4-dichlorobenzyl) -5- (4-chlorophenyl) -4-3-metyipyrazol carboxamide

This compound was prepared as described in Step B of Example 43, starting from 0.315 g of the compound obtained in Preparation 2.1, 0.46 ml. triethylamine and 0.653 g of the compound obtained in the previous stage at 50 ml. dichloromethane. 0.68 g of the expected product is obtained, m.p. = 125 ° C.

a ²⁰ _D = -0.3 ⁰ (c = 1, EtOH).

Example 46

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (3,4-dichlorobenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3 carboxamide

A. 1- (3,4-Dichlorobenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3-carboxylic acid chloride

This compound was prepared as described in Example 45, Step A, starting from 1 g of the compound obtained in Preparation 1.31 in 50 ml toluene and 0.28 ml thionyl chloride. 1.03 g of the expected product is obtained in the form of an oil which is converted to a solid.

B. N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3,4-dichlorobenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3- carboxamide

This compound was prepared as in Example 43, Step B starting from 0.315 g of the compound obtained in Preparation 2.1, 0.46 ml of triethylamine and 0.687 g of the compound obtained in the previous step in 50 ml of dichloromethane. 0.72 g of the expected product is obtained, m.p. = 69 ° C.

α ²⁰ D = -1.8 ° (c = 1, EtOH)

30983 / H

Example 47

N - [(18) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3-chloro-4-methylbenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3- carboxamide

A. 1- (3-Chloro-4-methylbenzyl) -5- (4-chlorophenyl) -4-methylpyrazole-3-carboxylic acid chloride

This compound was prepared as described in Example 45, Step A, starting from 1 g of the crude compound obtained in Preparation 1.32 in 50 ml of toluene and 0.29 ml of thionyl chloride. 1.05 g of the expected product is obtained.

B. N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3-chloro-4-methylbenzyl) -5- (4-chlorophenyl) -4-methylpyrazole- 3-carboxamide

This compound was prepared as described in Example 43, Step B starting from 0.29 g of the compound obtained in Preparation 2.1, 0.24 ml of triethylamine and 0.6 g of the compound obtained in the previous step in 50 ml of dichloromethane. 0.43 g of the expected product is obtained, m.p. = 58 ° C.

[α] ²⁰ _D = -1.7 ° C (c = 1, EtOH).

Example 48

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (4-methylbenzyl) -5- (4-chloro-3-methylphenyl) -4-methylpyrazole-3 carboxamide

A. 1- (4-Methylbenzyl) -5- (4-chloro-3-methylphenyl) -4-methylpyrazole-3-carboxylic acid chloride

To a suspension of 1.5 g of the compound obtained in Preparation 1.33 in 40 ml of toluene was added 1 ml of thionyl chloride and heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in toluene and the solvent was evaporated in vacuo. 1.5 g of the expected product are obtained.

B. N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (4-methylbenzyl) -5- (4-chloro-3-methylphenyl) -4-methylpyrazole- 3-carboxamide

This compound was prepared as described in Example 43, Step B starting from 0.42 g of the compound obtained in Preparation 2.1, 0.7 ml of triethylamine and 0.8 g of the compound.

C 98.3. Obtained in the previous stage 40 ml of dichloromethane. In this way it is obtained

0.62 g of the expected product, m.p. = 58 ° C.

and ² ° D = -2.4 ° (c = 1, EtOH).

Example 49

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (3,4-dichlorobenzyl) -5- (4-chloro-3-methylphenyl) -4-metylpyrazol- 3-carboxamide

A. 1- (3,4-Dichlorobenzyl) -5- (4-chloro-3-methylphenyl) -4-methylpyrazole-3-carboxylic acid chloride

To a suspension of 2.7 g of the compound obtained in Preparation 1.34 in 50 ml of toluene was added 1.5 ml of thionyl chloride and heated to reflux for 2 hours. The reaction mixture was concentrated in vacuo, the residue was taken up in toluene and the solvent was evaporated in vacuo. 2.8 g of the expected product are obtained.

B. N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3,4-dichlorobenzyl) -5- (4-chloro-3-methylphenyl) -4- methylpyrazole-3-carboxamide

This compound was prepared as described in Example 43, step B starting from 0.683 g of the compound obtained in Preparation 2.1, 1.2 ml of triethylamine and 1.5 g of the compound obtained in the previous step in 40 ml of dichloromethane. 1.03 g of the expected product is obtained, m.p. = 69 ° C.

a ²⁰ D = -2.1 ° (c = 1, EtOH).

Example 50

N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3-chloro-4-methylbenzyl) -5- (4-chlorophenyl) -4- (ethoxymethyl) pyrazole-3-carboxamide

A. 1- (3-Chloro-4-methylbenzyl) -5- (4-chlorophenyl) -4- (ethoxymethyl) pyrazole-3-carboxylic acid chloride

To a solution of 0.2 g of the compound obtained in Preparation 1.35 in 30 ml of toluene is added 0.053 ml of thionyl chloride and heated to reflux for 2 hours. It is concentrated under vacuum, the residue is taken up in toluene and the solvent is evaporated off under vacuum.

and

0.21 g of the expected product is obtained in the form of an oil. /

30983.Ή

B. N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (3-chloro-4-methylbenzyl) -5- (4-chlorophenyl) -4- (ethoxymethyl) ) pyrazole-3-carboxamide

This compound was prepared as described in Example 40, Step B starting from 0.086 g of the compound obtained in Preparation 2.1 in 25 ml of dichloromethane, 0.125 ml of triethylamine and 0.2 g of the compound obtained in the previous step in 25 ml of dichloromethane. 0.15 g of the expected product is obtained, m.p. = 50-51 ° C.

Example 51

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (5-chloroindan-1-yl) -5- (4-chlorophenyl) pyrazole-3-carboxamide

A. 1- (5-Chloroindan-1-yl) -5- (4-chlorophenyl) pyrazole-3-carboxylic acid chloride

To a suspension of 1 g of the compound obtained in Preparation 1.36 at 20 ml. of toluene is added 0.6 ml of thionyl chloride and heated to reflux for 2 hours. After cooling to ambient temperature, it is concentrated under vacuum, the residue is taken up in toluene and the solvent is evaporated off under vacuum. 1 g of the expected product is obtained.

B. N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (5-chloroindan-1-yl) -5- (4-chlorophenyl) pyrazole-3-carboxamide

To a solution of 0.493 g of the compound obtained in Preparation 2.1 and 1 ml of triethylamine in 15 ml of dichloromethane is added dropwise a solution of 1 g of the compound obtained in the previous stage in 15 ml of dichloromethane and left to stir at room temperature overnight. Concentrate in vacuo, remove the residue in AcOEt, filter the insoluble matter, wash the filtrate with saturated aqueous NaHCO 3, pH = 2, saturated aqueous NaCl, dry over Na ₂ SO ₄ and evaporate the solvent in vacuo. The residue is chromatographed on silica gel eluting with cyclohexane / AcOEt (80/20, v / v). 0.71 g of the expected product is obtained, m.p. = 86 ° C.

α ²⁰ _D = + 0.5 ° (c = 1, EtOH)

NMR: .delta. (Ppm): 0.4-1.8, m, 16H, 2.5, mt, 2H, 2.95, mt, 2H, 3.5, d, 1H, 5.8, t, 1H 6.6 to 7.7, m, 9H.

3 (983/13

An Overhauser effect (N.O.E.) was observed between the proton at position 1 of the indan-1-yl group and the protons g2 = g6 = H.

Example 52

1- (3,4-Dichlorobenzyl) -5- (4-methylphenyl) pyrazole-3-carboxylate (1 R) -1,3,3-trimethylbicyclo [2.2.1] hept-2-en-yl

A mixture of 1.5 g of the compound obtained in step A of Example 1, 0.73 g of (1R) -endo - (+) phenchyl alcohol, 50 ml of pyridine and 0.02 g of 4-dimethylaminopyridine is left under stirring at ambient temperature for 72 hours. The reaction mixture is concentrated in vacuo and the residue is chromatographed on silica gel eluting with dichloromethane. 0.23 g of the expected product is obtained, m.p. = 107 ° C.

α ² D = + 6.8 ^° (c = 1, methanol).

Example 53

- (3-chloro-4-methylbenzyl) -5- (3,4-dichlorophenyl) pyrazole-3-carboxylate (1R) -1,3,3-trimethylbicyclo [2.2.1] hept-2-en-yl

To a solution of 2.6 g of the compound obtained in Step A of Example 36 in 50 ml of pyridine is added 0.97 g of (1R) -endo - (+) - fenchyl alcohol and 0.02 g of 4-dimethylaminopyridine, and then left for 48 hours. hours with stirring at ambient temperature. It is concentrated under vacuum, the residue is taken up in ether, the precipitate formed is drained and dried. The precipitate is chromatographed on silica gel eluting with cyclohexane / AcOEt / dichloromethane (85/15/3, v / v). 0.40 g of the expected product is obtained, m.p. = 161 ° C.

α ²⁰ ο = + 3,9 ° (c = 1, dichloromethane)

Example 54

N - [(1S) -1,3,3-Trimethylbicyclo [2.2.1] hept-2endo-yl] -1- (2,4-dichlorobenzyl) -3- (4-chlorophenyl) pyrazole-5-carboxamide

A. 1- (2,4-Dichlorobenzyl) -3- (4-chlorophenyl) pyrazole-5-carboxylic acid chloride

To a suspension of 0.79 g of the compound obtained in Preparation 1.38 in 20 ml of toluene was added 0.54 ml of thionyl chloride and heated to reflux for 3 hours.

3C98

It is concentrated under vacuum, the residue is taken up in 20 ml of toluene and the solvent is evaporated off under vacuum. 0.9 g of the expected product is obtained.

B. N - [(1S) -1,3,3-trimethylbicyclo [2.2.1] hept-2-eno-yl] -1- (2,4-dichlorobenzyl) -3- (4-chlorophenyl) pyrazole-5-carboxamide

A solution of 0.21 g of the compound obtained in Preparation 2.1 and 0.3 ml of triethylamine in 10 ml of dichloromethane is cooled to 0 ° C, a solution of 0.45 g of the compound obtained in the previous step in 15 ml of dichloromethane is added dropwise. is stirred for 16 hours at ambient temperature. The reaction mixture was poured into 100 ml of ice-water, extracted with dichloromethane, the organic phase is washed with water, saturated NaCl, dried over Na ₂ SO ₄ and the solvent evaporated in vacuo. 0.37 g of the expected product is obtained after crystallization in a dichloromethane / iso ether mixture, m.p. = 171 ° C.

a ²⁰ _D = -3.2 ° (c = 0.5, EtOH)

Example 55

Gelatin capsules Example compound 181 mg modified corn starch47 mg lactose monohydrate EFK 150 m and magnesium stearate2 mg

White opaque capsule, size 3: 200 mg

Example 56

Gelatin Capsules Example compound 1830 mg modified corn starch30 mg magnesium stearate2 mg lactose monohydrate EFKQ / S

White opaque capsule, size 3:

200 mg

Example 57

tablets

the compound of Example 18 10 mg PVP (polyvinylpyrrolidone) K30 4.5 mg reticulated sodium carboxymethylcellulose 3 mg magnesium stearate 1.5 mg lactose monohydrate 200 mesh Q / S purified water Q / S Divisible tablet 150 mg Example 58 Gelatin capsules the compound of Example 48 30 mg hydroxypropylmethylcellulose 6mPas 7,5 mg lactose monohydrate 200 mesh Q / S magnesium stearate 2,5 mo purified water Q / S Size 1 capsule: 250 mg Example 59 tablets the compound of Example 48 40 mg maize starch 50 mg PVP K30 9 mg carboxymethylated sodium starch 9 mg magnesium stearate 3 mg lactose monohydrate 200 mesh Q / S

Divisible tablet 300 mg

Claims (23)

PATENT CLAIMS A compound of formula (I) wherein the symbol X 1 is -NR 4 or OR ₂ , g ₂ , g ₃ , g ₄ , g ₅₁ g _{6 and} w ₂ , w ₃ , w ₄ , w ₅ , w ₆ are identical or different and are each independently hydrogen, a halogen atom, a (C ₁ -C ₄ ) alkyl group. _(Ci-C4) alkoxy, trifluoromethyl, nitro, (C _r C ₄₎ alkylthio; WS, provided that at least one of the substituents g _2, g _3, g _4, g _5, g ₆ and at least one of the substituents w _2, w _3, w _4, w _5, w ₆ are other than hydrogen, R 1 represents a hydrogen atom or a (C 1 -C ₄ ) alkyl group, R ₂ represents a carbocyclic non-aromatic radical having (C ₃ -C ₁₅ ) carbon atoms, unsubstituted or substituted one or more times with substituents selected from the group consisting of halogen, (C 1 -C ₄ ) alkyl or C 1 -C ₄ ) alkoxy, R ₃ represents a hydrogen atom or a group -CH ₂ -R ₆ , R ₄ and R 5 are each independently hydrogen, (C _{r C4)} alkyl or a trifluoromethyl, or else R ₄ is H and R 5 and w ₆ which together form ethylene or trimethylene radical, 3098. 2 101 R ₆ represents a hydrogen atom or when the substituents g ₂ , g ₃ , g ₄ , g ₅ and / or g ₆ are other than a (C 1 -C ₄ ) alkyl group, R 6 represents a hydrogen atom, a (C 1 -C ₄ ) alkyl group, an atom fluoro, hydroxy, (C 1 -C 5) alkoxy, (C ^ -C) alkylthio, hydroxy (C -C) alkoxy, cyano, (C 1 -C 5) alkylsulfinyl, (C _r C) alkylsulfonyl, such as the salt. A compound of formula (I) according to claim 1, wherein X 1 is -NR 1 R 2 wherein R 1 is hydrogen, as well as salts thereof. A compound of formula (I) according to claim 1, wherein X 1 is -NR 1 R ₂ , or -OR 2, wherein R ₂ is a 1,3,3 trimethylbicyclo [2.2.1] -hept-2-yl radical or a radical bicyclo [3.2.1] oct-3-yl, and salts thereof. Compound of formula (I) according to claim 1, in which R 3 represents a hydrogen atom or a group -CH 2 -R 6, in which R 6 represents a hydrogen atom, and salts thereof. A compound of formula (I) according to claim 1, wherein either R ₄ and R ₅ represent each hydrogen atom or R ₄ represents a hydrogen atom and R 5 represents a (C 1 -C ₄ ) alkyl group and salts thereof. A compound of formula (I) according to claim 1, wherein g ₂ , g ₅ and g ₆ represent each hydrogen atom and g _{3 and} g ₄ are as defined for compounds of formula (I) in claim 1 as well as salts thereof. A compound of formula (I) according to claim 1, wherein W 5 and w = each hydrogen, w ₄ represents a halogen atom, a (C 1 -C ₄ ) alkyl group, a (C 1 -C ₄ ) alkoxy group, trifluoromethyl or (C 1 -C ₄ ) alkyl. -C ₄ ) alkylthio and either w ₂ and W 3 are each hydrogen or one of them is hydrogen and the other is halogen, (C ₁ -C ₄ ) alkyl or trifluoromethyl, and salts thereof. Compound according to claim 1 of the general formula (Ia) 30983 102 wherein the substituents R 2 R ₂ are the same as defined for compounds of formula (i) in claim 1, R _3a represents a hydrogen atom or a group -CH ₂ -R _6a , R _6a represents a hydrogen atom or provided that the substituents g _{3a and} g _4a are other than a (C ₁ -C ₄ ) alkyl group, R _6a is H, methyl or ethyl, g ₃ is H, halogen, _(Ci-C4) alkyl or a trifluoromethyl, 'g of _{4 a} is halogen, _(Ci-C4) alkyl, or trifluoromethyl, w ₄ is halogen, _(Ci-C4) alkyl, or trifluoromethyl, w ₂ and w ₃ groups are each hydrogen or one is hydrogen and the other is halogen, _(Ci-C4) alkyl or a trifluoromethyl; and its salts. Compound according to claim 1 of the general formula (Ib) (Ib) 309S3 / 103 wherein the substituents: R 1, R ₂ are the same as defined for the compounds of formula (I) in claim 1, R 3a, g 3a, g 4a, w _2a , w _{3a and} w _4a are the same as defined for the compounds of formula (Ia) in claim 8, Rsb represents a (C ₁ -C ₄ ) alkyl group and salts thereof. A compound according to claim 1 of the general formula (Ic) (Ic) wherein the substituents: R ₂ is as defined for compounds of formula (I) in claim 1. R _3a , W _2a , w _3a , w _4a , g _{3a and 4a} are the same as defined for compounds of formula (Ia) in claim 8 as well as salts thereof. Process for the preparation of the compounds of the general formula (I) according to claim 1 and their salts, characterized in that they are: 1. acts on a functional pyrazole-3-carboxylic acid derivative of the general formula (II): 30983 / H 104 »in which the substituents w _2, w _3, w _4, w _5, w _6, g _2, g _3, g _4, gs, g6. R 3, R 4 and R ₅ are as defined for the compounds of formula (I) in claim 1; a compound of formula (XXIV): Η-Χτ (XXIV) wherein the group X 1 is as defined for compounds of formula (I) in claim 1, 2. and optionally converting the compound thus obtained into one of its salts. A process according to claim 11 for the preparation of compounds of formula (I) _: wherein X 1 is represented by NR ₁ R ₂ and salts thereof, characterized in that: 1. acts on a functional pyrazole-3-carboxylic acid derivative of formula (II) as defined in claim 11, with an amine of formula (III): HNR ₁ R ₂ (III) wherein R 1 and R ₂ are as defined for compounds of formula (I) in claim 1, 2. and optionally converting the compound thus obtained into one of its salts. A process according to claim 11 for the preparation of compounds of formula (I) wherein X 1 is represented by -OR ₂ and salts thereof, characterized in that: 30983 105 1. acts on a functional pyrazole-3-carboxylic acid derivative of formula (II) as defined in claim 11 with an alcohol of formula (XIV): HO-R ₂ (XIV) wherein R ₂ is as defined for compounds of formula (I) in claim 1, 2 and optionally converting the compound thus obtained into one of its salts. A compound of formula (XIII) (ΧΠΙ) wherein: Xi, g2. g3, g4, g6, _{w2, w3, w4, w5)} w _6, R 3 and R ₅ are as defined for the compounds of formula (I) in Claim 1, and salts thereof. A process for the preparation of the compounds of formula (II) as defined in claim 11 and compounds of formula (XII): (XII) 30983 / H 106 in which: g _2, g with g _4, gs, g6, _{w2, w3, w4, w5,} w _6, R ₃ and R 5 are as defined for the compounds of formula (I) in Claim 1, characterized by getting 1. acts on a compound of formula (XXV): COOAlk (XXV) wherein g ₂ , g ₃ , g ₄ , g ₅ , g ₆ and R ₃ are as defined above and Alk represents a methyl or ethyl group, with a strong base in a solvent ξ then leaving the anion thus obtained react with a compound of formula (VII) (VII) wherein w ₂ , w ₃ , w ₄ , W 5, we, and R 5 are as defined above and Hal represents a halogen atom to give: - either when the reaction is carried out in toluene at a temperature between ambient temperature and the reflux temperature of the solvent, the compound of formula (XXVI): (XXVI) 30983, Ή 107 - or, when the reaction is carried out in Ν, Ν-dimethylformamide at a temperature between 0 ° C and ambient temperature, the compound of formula (XXVII): (XXVII) 2. hydrolyzes in an alkaline medium either a compound of formula (XXVII) or a compound of formula (XXVII) to give: - either a compound of formula (II, R ₄ = H): -Q (II: R ₄ = H) - or a compound of formula (XII): (XII) Process for the preparation of the compounds of the general formula (XIII) according to claim 14 and their salts, characterized in that they are: 30983 i-: 108 1. treating a functional acid derivative of formula (XII) as defined in claim 15 with a compound of formula (XXIV): H - X 1 (XXIV) wherein X 1 is as defined for compounds of formula (I) in claim 1 to give a compound of formula (XIII): (Χίπ) And optionally converting the compound to one of its salts. A compound according to any one of claims 1 to 10 or 14 in radiolabelled form. A pharmaceutical composition comprising as an active ingredient a compound according to any one of claims 1 to 10, or a pharmaceutically acceptable salt thereof. The pharmaceutical composition of claim 18 in unit dosage form, wherein the active ingredient is admixed with at least one pharmaceutical excipient. A pharmaceutical composition according to claim 19 comprising from 0.5 to 1000 mg of the active ingredient. A pharmaceutical composition according to claim 20 comprising from 2.5 to 250 mg of the active ingredient. The use of the compounds according to any one of claims 1 to 10, or pharmaceutically acceptable salts thereof, for the preparation of medicaments intended for the treatment of conditions in which CB ₂ receptors act. Use of the compounds according to any one of claims 1 to 10, 14 or 17 as pharmacological tools.